sign in sign up
<<
Home , Nanomaterials, Nanotechnology

Emerging issues | — early lessons from early warnings

22 Nanotechnology — early lessons from early warnings

Steffen Foss Hansen, Andrew Maynard, Anders Baun, Joel A. Tickner and Diana M. Bowman

Nanotechnology is the latest in a long series of heralded as ushering in a new era of -driven prosperity. Current and applications of nanotechnology are expected to lead to substantial societal and environmental benefits, increasing economic development and employment, generating better materials at lower environmental costs, and offering new ways to diagnose and treat medical conditions. Nevertheless, as new materials based on nanoscale move from the lab to the marketplace, have we learnt the lessons of past 'wonder technologies' or are we destined to repeat past mistakes?

This chapter first introduces nanotechnology, clarifies the terminology of and describes current uses of these unique materials. Some of the early warning signs of possible adverse impacts of some nanomaterials are summarised, along with regulatory responses of some governments. Inspired by the EEA's first volume of Late lessons from early warnings, the chapter looks critically at what lessons can already be learned, notwithstanding nanotechnology's immaturity (1).

Nanotechnology development has occurred in the absence of clear design rules for and materials developers on how to integrate health, safety and environmental concerns into design. The emerging area of '' offers promise for the future with its focus on preventive design. To gain traction, however, it is important that research on the sustainability of materials is funded at levels significant enough to identify early warnings, and that regulatory systems provide incentives for safer and sustainable materials.

Political decision-makers have yet to address many of the shortcomings in legislation, , and limitations in risk assessment, management and governance of and other . As a result, there remains a developmental environment that hinders the adoption of precautionary yet socially and economically responsive strategies in the field of nanotechnology. If left unresolved, this could hamper society's ability to ensure responsible development of nanotechnologies.

(1) This chapter is based on and in parts identical to Hansen, S.F., Maynard, A., Baun, A., Tickner, J.A. 2008. 'Late lessons from early warnings for nanotechnology', Nature Nanotechnology, (3/8) 444–447.

530 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

22.1 What is nanotechnology and what Although the definition is broad, in most materials are nanomaterials? or systems it can be determined whether they involve nanomaterials or not (Hansen et al., 2007). Nanotechnology is often described as having roots in a wide range of scientific and technical fields, The range of nanomaterials that can be including , , , material manufactured is extremely broad. However the science and . The field of nanotechnology techniques used to produce them can, roughly is thus broad and covers a multitude of materials, speaking, be divided into top-down and bottom‑up techniques, scientific and commercial applications approaches. Top-down techniques involve starting and products (RS and RAE, 2004). Originally the from a larger unit of material, and etching or term nanotechnology, first used by Taniguchi in 1974, milling it down to smaller units of desired shape, referred to the ability to materials precisely whereas bottom-up involves progressing from at the nanometre (nm) level (Taniguchi, 1974). The smaller sub‑units (e.g. or ) to make term has since been framed and reframed by various larger and functionally richer structures (RS and actors over the decades and, despite the desire for a RAE, 2004; BSI, 2007b). Top-down techniques unifying all embracing definition of nanotechnology, include processes such as high-energy ball milling, many versions of the definition exist today. Here, we etching, sonication and ablation, whereas use the widely-accepted definition suggested by the bottom‑up techniques include sol-gel, chemical United States National Nanotechnology Initiative vapour deposition, or flame spraying, (NNI): supercritical fluid, spinning and self-assembly (Biswas and Wu, 2005). Both approaches pose Nanotechnology is the understanding and specific challenges. Creating smaller and smaller control of at dimensions between structures with sufficient accuracy is a critical approximately 1 and 100 nanometers, challenge for top‑down manufacturing, whereas where unique phenomena enable novel the challenge for bottom-up techniques is to make applications. Encompassing nanoscale science, structures large enough and of sufficient quality engineering, and technology, nanotechnology (RS and RAE, 2004). involves imaging, measuring, modelling, and manipulating matter at this length scale Starting with a palette of conventional materials, (NNI, 2009). new nanomaterials may be formed by subtly altering the shape, size and form of these materials Chemistry typically deals with large numbers of at the nanoscale. A further range of nanomaterials atoms and molecules acting together. The behaviour with new properties may be developed by of individual atoms and molecules can best be combining two or more nanoscale materials. understood within a quantum physics‑based Familiar chemicals may also be used to construct framework, while the motion of massive collections new nanometre‑scale molecules and structures, of atoms and molecules such as physical objects such as -60 and carbon-70 molecules under the influence of are best described (C60 and C70), carbon nanotubes, nanoscale through classical mechanics or Newtonian physics. liposomes, self‑assemble monolayers, dendrimers Nanotechnology falls between these two domains and . Various international standardisation and holds the possibility of revealing and exploiting institutes have expanded their focus of attention unique novel phenomena as a result. from trying to define nanotechnology to defining the nature of the many different kinds of Although the wordings differ, a number of definitions nanomaterials such as carbon , require that two criteria must be fulfilled for materials and nano-objects (BSI, 2007; ISO, 2008). to be considered as engineered nanomaterials (2): In order to facilitate hazard identification and • they must have some purposely engineered focus risk assessment, a procedure for dividing structure with at least one dimension in the nanomaterials into relevant subcategories has been approximate range 1–100 nm; developed by Hansen et al. (2007), as illustrated by Figure 22.1. • this must give the system properties that differ from those of the bulk forms Hansen et al. (2007) suggest categorisation of of the same material. nanomaterials depending on the location of the

(2) Nanomaterials in this context specifically refer to materials that have been purposely engineered to have nanoscale structure.

Late lessons from early warnings: science, precaution, innovation 531 Emerging issues | Nanotechnology — early lessons from early warnings

Figure 22.1 The categorisation framework for nanomaterials. The nanomaterials are categorised according to the location of the nanostructure in the material

Source: Hansen et al., 2007, reprinted with permission.

nanoscale structure in the system. This leads to a between 1 and 100 nanometre (3). Category III above division of nanomaterials into three main categories: contains nanostructured that can have various forms and shapes and this category • materials that are nanostructured in the bulk; includes, for example, quantum dots, , nanotubes and (Maynard and Aitken, • materials that have nanostructure on the surface; 2007). There are four subcategories of systems with nanoparticles, depending on the environment • materials that contain nanostructured particles. around the nanoparticles:

Nanoparticles have been defined by the ISO (2008) • subcategory IIIa has nanoparticles bound to the as particles having three external dimensions surface of another structure;

(3) It is important to note that this is not a universally accepted definition and that, as with the term nanotechnology, a number of different definitions as to what constitutes a nanomaterial exists. The articulation by the European Commission of their recommendation for a definition is discussed in detail in Section 22.5 of this chapter.

532 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

• subcategory IIIb consists of systems where scientific research publications in nanotechnology nanoparticles are suspended in a liquid; (Linkov et al., 2009). Scientific activities sparked by government funding have had a crucial role in • subcategory IIIc is nanoparticles suspended in nanotechnology-related knowledge creation and ; technology transfer, although there is often some time lag before scientific knowledge is diffused into useful • subcategory IIId consists of airborne inventions and applications (Igami and Okazaki, nanoparticles. 2007).

Most health and environmental impact concerns have been raised over nanoparticles that fall into 22.3 Current production and subcategories IIIc and IIId (see, for example, application of nanotechnology and SCENIHR, 2009; RCEP, 2008; Madl and Pinkerton, nanomaterials 2009). A major benefit of the proposed categorisation framework is that it provides a tool for dividing According to the Nanotechnology Company nanosystems into identifiable parts, thereby Database, there are now about 2 000 nanotechnology- facilitating evaluations of, for example, relevant focused companies around the world; the majority exposure routes or analysis of effect studies of these are based in the US (estimates suggest according to relevance to the material tested. 1 100), and 670 have their headquarters within the European Union (Nanowerk, 2010). These companies range from multinationals to small and medium-size 22.2 Development of nanotechnology companies and university spin-offs. They span a wide and nanomaterials range of sectors and applications including energy, analysis, textiles, anti-microbial wound dressings, The development of nanotechnology has been rapid paints and coatings, fuel catalysts and additives, when assessed by a number of metrics, including lubricants, cosmetics and food packaging (Chaundry government funding and number of research et al., 2006; Hodge et al., 2010). publications and industrial (see, for example, Chen and Roco, 2009; Youtie et al., 2008; Sylvester and Till now, the emerging nature of the technology has Bowman, 2011). Early nanotechnology development ensured that much of the public and private sector was driven by advances in and attention has been on R&D activities. However, one scientific breakthroughs such as the discovery of could argue that nanotechnology is entering in a new fullerenes, quantum dots and carbon nanotubes era in which both the number of products containing (Iijima, 1991) along with innovations that allowed nanomaterials and the sophistication of these nanostructures to be visualised, such as the invention nanomaterials have increased spectacularly. Mundane of the scanning tunnelling and the atomic products will soon, it would appear, be superseded force microscope (Kroto et al., 1986; Iijima, 1991; by a range of innovative nanotechnology‑based Binning et al., 1982 and 1986). products.

One of the key turning points in science and In 2006, the Project for Emerging Nanotechnologies technology policy in relation to nanotechnology was (PEN) at the Woodrow Wilson International the establishment of the National Nanotechnology Center for Scholars launched an online inventory Initiative (NNI) by the United States of America of consumer products that are reported to include (USA) Government in 2000, along with significant nanomaterials (the Consumer Products Inventory). increases in research and development (R&D) At the time of its launch in March 2006, the funding for nanotechnology-related research (Igami global inventory contained 212 different products and Okazaki, 2007). Since then, most developed and available for purchase. This number increased many emerging economies have launched national to 580 products in 2007, and in March 2011 the initiatives or prioritise research in nanotechnology inventory contained 1 317 products from about (Roco, 2011). Although somewhat speculative in 30 countries (PEN, 2011). These products fall into nature, Lux Research (2008) estimated that in 2008 a number of different categories including health alone global nanotechnology R&D investment was and fitness, home and garden, and electronics and around USD 18.2 billion, representing USD 8.4 billion computers. More than half (738) were considered to from governments, USD 8.6 billion from corporate be health and fitness‑related and included products sources and USD 1.2 billion from venture capital as diverse as straighteners, sporting equipment investors. Government funding of academic research and cosmetics. The primary material in many of has lead to a significant increase in the number of the products was nanoscale silver (PEN, 2011). The

Late lessons from early warnings: science, precaution, innovation 533 Emerging issues | Nanotechnology — early lessons from early warnings

Woodrow Wilson Consumer Products Inventory on ultrafine particles has found an increased contains information such as product name, morbidity and mortality from cardiovascular and company, manufacturer or supplier, country of pulmonary diseases inversely correlated with size origin, and a short product description. However, i.e. the smaller the particles, the more dangerous it does not contain information about how many (Oberdorster et al., 2005a; Pope and Dockery, 2006). units of a given product are produced and sold or Since nanomaterials are in the same size range the mass/volume of nanomaterial in each product. as ultrafine particles, concerns have been raised Such information is only available if the producers on whether nanomaterials could have the same themselves make it available, which occurs rarely. It hazardous properties as ultrafine particles. is therefore not surprising that the public, and even the relevant regulators themselves, have limited Much of the research performed on ultrafine knowledge about the current production volumes particles in the 1990s now feeds into what we know of nanomaterials. Moreover, the veracity of the about the potential risk of nanomaterials and lays available information must be considered, given its the foundation for many of the current scientific scattered and incomplete nature. research hypotheses in the field of nano(eco) toxicology (Oberdorster et al., 2007). One of the Publicly available information on commercially most important hypotheses is that the hazard produced engineered nanomaterials is at best properties of nanoparticles might be related to patchy. For example, in 2001, the global production inherent physico-chemical properties different from of carbon-based nanomaterials was estimated to be those traditionally used for industrial chemicals, around several hundred tonnes per year; by 2003 e.g. , shape, crystal structure, surface global production of nanotubes alone was estimated area, surface chemistry and surface charge. As to be about 900 tonnes (Kleiner and Hogan, 2003). early as 1990 Oberdorster et al. (1990) and Ferin Frontier Carbon Corp, a Japanese-based company, et al (1990) reported that ultrafine

produces more than 40 tonnes of C60 per annum, (TiO2) and aluminium oxide (Al2O3) of 30 and mainly for use in a range of goods including 20 nm, respectively, induced a very striking sporting goods, batteries, lubricants and inflammatory reaction in the lung of rats compared additives (Fujitani et al., 2008). The consulting firm to larger particles of 250 and 500 nm. Two years Cientifica (2006) has estimated that in 2006 the later Oberdorster et al. (1992) reported that the

global annual production of nanotubes and fibres crystallinity of TiO2 nanoparticles influenced their was 65 tonnes, giving it a commercial value of about toxicity and that surface area was a better descriptor EUR 144 million. Cientifica (2006) has suggested than mass for the adverse effects observed in rats. that the value of nanotubes and fibres will exceed Donaldson et al. (2002) have since observed a EUR 3 billion by 2010, representing an annual similar correlation for , when studying growth rate of well over 60 %. The veracity of these the ability of nano and micron particles to cause claims is still to be tested. Even though information inflammatory effects in rats. Warheit et al. (2006) about the production of carbon-based nanomaterials and Sayes et al. (2007), however, did not observe is scarce, more is known, or at least guessed at, any correlation with surface area when evaluating about such materials than about many other biological response in rats after exposure to

nanomaterials such as quantum dots, nano- nano‑sized TiO2, SiO2 and other particles. and materials with nanostructured surfaces. One study has found a statistically significant increase in malignant lung tumours in rats

22.4 Signs of early warnings following chronic inhalation of nano-sized TiO2 (Heinrich et al., 1995) and, on the basis of this study,

Concerns have been raised about the potential risks NIOSH (2011) has determined that ultrafine TiO2 of nanotechnology and nanomaterials almost since should be considered a potential occupational

the emergence of nanotechnology (Drexler, 1986), carcinogen. NIOSH further concluded that TiO2 and historical analogies have been made with both is not a direct‑acting carcinogen, but acts through ambient ultrafine particles and (RS and a secondary genotoxicity mechanism that is not

RAE, 2004; Seaton et al., 2009; Mullins, 2010). specific to TiO2 but primarily related to particle Ambient ultrafine particles, which can come from size and surface area and surface area was found multiple sources, are defined as airborne nanoscale to be the critical metric for occupational inhalation

particles, including particles incidentally produced exposure to TiO2. such as those in diesel exhaust and incinerator stacks. Ultrafine particles are typically considered to Visual similarities between carbon nanotubes be smaller than 0.1 micron (i.e. < 100 nm). Research (CNTs) and asbestos fibres have led to others raising

534 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

concerns about them having the same hazardous (2009) and Pauluhn (2010). For example, in a 90-day properties (Huczko et al., 2001; Warheit, 2009). In nose‑only inhalation toxicity study of MWCNTs, 2004 Lam et al. (2004) published a study in which Ma‑Hock et al. (2009) found that the incidence they exposed mice to a number of single‑walled and severity of granulomatous of CNTs of different purity and found that all the lung and the lung-draining lymph nodes were nanotubes induced dose-dependent concentration‑dependent, something which has and interstitial inflammation in the lungs. The previously been demonstrated for intra-tracheally results presented by Lam and co-workers were instilled single-walled carbon nanotubes (SWCNTs) supported by observations by Warheit et al. (2004) (Lam et al., 2004) and MWCNTs (Muller et al., 2005). who also observed pulmonary granulomas in rats Interestingly, exposure via inhalation revealed after exposure to single-walled CNT soot. However, inflammation in the nasal cavity, larynx and trachea, in contrast to Lam et al., the effects observed by where the particles are deposited during inhalation, Warheit et al. (2004) were not dose-dependent. as well as alveolar lipoproteinosis. This had not been Absence of pulmonary biomarkers suggests a observed using intra-tracheal or intra-peritoneal potentially new mechanism of pulmonary toxicity administration (Ma-Hock et al., 2009). and induced injury (Warheit et al., 2004). More recently, Poland et al. (2008) compared the toxicity In addition to CNTs, substantial concerns have of four kinds of multi-walled carbon nanotubes been raised over the use of nanometre‑scale silver (MWCNTs) of various diameters, lengths, shape and particles, or nanosilver, especially in regard to its chemical composition by exposing the mesothelial widespread prevalence in everyday consumer lining of the body cavity of three mice to 50 mg products. Nanosilver is reportedly one of the most MWCNT for 24 hours or 7 days. This method was widely used nanomaterials in consumer products used as a surrogate for the mesothelial lining of today (PEN, 2011), and the antibacterial properties the chest cavity. They found that long MWCNTs of nanosilver have been exploited in a very diverse produced length dependent inflammation, set of products and applications. These include foreign body giant cells and granulomas that were dietary supplements, personal-care products, qualitatively and quantitatively similar to the powdered colours, varnish, textile, , interior foreign body inflammatory response caused by long and exterior paints, printing colours, water and air asbestos. Only the long MWCNTs caused significant purification, polymer-based products and foils for increase in polymorphonuclear leukocytes or antibacterial protection such as washing , protein exudation. The short MWCNTs failed to kitchenware and food storage (PEN, 2011). The cause any significant inflammation at 1 day or scale of use is currently unknown as there are no giant formation at 7 days. The finding that the labelling requirements for nanoproducts, and the length of CNTs affects their biological activity is concentrations used are also unknown for most of supported by findings by Takagi et al. (2008) and the products on the market (Boxall et al., 2008). Muller et al. (2009). Poland et al. (2008) also found that water‑soluble components of MWCNTs did not Many applications involving nanosilver involve direct produce significant inflammatory effects 24 hours exposure of the substance to humans. This has raised after injection, which rules out the concern that concern about the potential human health effect of residue metals were the cause of the observed the material. The potential health and environmental effects, an association that other researchers had impacts of nanosilver have been subject to many previously hypothesised on the basis of in vitro reviews (Luoma, 2008; Aitken et al., 2009; Wijnhoven studies (Shvedova et al., 2005; Kagan et al., 2006). et al., 2009; Pronk et al., 2009; Stone et al., 2010, Christensen et al., 2010; Mikkelsen et al., 2011). The Most studies of CNTs have used intra-tracheal toxicity of silver is generally considered to be or intra-peritoneal administration. Intra-tracheal relatively low (Wijnhoven et al., 2009). At very high and intra-peritoneal instillation bypasses upper concentrations, repeated ingestion or inhalation of respiratory tract defences and does not deposit colloidal silver has been found to lead to deposition particles evenly in the lung in a manner similar of silver metal/silver sulphide particles in the , to inhalation. This has historically led to the eye and other organs, leading to blue or bluish-grey biological relevance of such studies being discolouration of the skin. Although cosmetically questioned (Oiser et al., 1997). Recently, however, undesirable and irreversible, the condition — known a number of nose-only inhalation studies on as argyria — is not life threatening. It has been CNTs have been published in peer-reviewed shown that silver from nanoparticles can enter the journals by industry (BASF, Nanocyl and Bayer) body via oral and inhalation routes and that silver that support previous findings such as Ellinger- is absorbed and distributed to target organs such as Ziegelbauer and Pauluhn (2009), Ma-Hock et al. the liver, olfactory bulb, lungs, skin, brain, kidneys

Late lessons from early warnings: science, precaution, innovation 535 Emerging issues | Nanotechnology — early lessons from early warnings

and testes (Sung et al., 2008 and 2009; Kim et al., be the case for elemental silver nanoparticles, but 2008). The form in which the silver is transmitted the influence of speciation on uptake, depuration through and accumulated within the body is however and toxicity has yet to be studied in depth. The unclear, i.e. whether it is present as particles, ions or environmental concentrations resulting from the use complexes (Mikkelsen et al., 2011). Nanosilver has of nanosilver in consumer products are at present been associated with inflammation as well as slight uncertain, although a number of different estimates liver damage in mice after oral exposure (Cha et al., have been made (e.g. Mueller and Nowack, 2008; 2008; Kim et al., 2008). Prolonged exposure to Gottschalk et al., 2010). Where silver nanoparticles nanosilver particles via inhalation has been found to are incorporated in textiles, they can be released produce an inflammatory response in the lungs of during washing (Benn et al., 2010). Resulting rats, as well as inducing alterations in lung function environmental concentrations in the low ng/L range (Sung et al., 2008). have been proposed by Gottschalk et al. (2010). It remains uncertain whether silver nanoparticles A number of in vitro studies have found that the are more toxic than their bulk counterpart or ionic toxicity of nanosilver is mediated by an increase silver, since the effects can in many cases be ascribed in the production of reactive oxygen species, to the ionic form of silver (Ag+). Some studies have stimulating inflammation and subsequent cell documented a more pronounced effect associated death. The relevance of this is unclear and subject with nanosilver (e.g. Navarro et al., 2008), but the to scientific investigation (Stone et al., 2010; data so far are not conclusive. Christensen et al., 2010; Mikkelsen et al., 2011). In an extensive review of risk assessments of nanosilver, After reviewing the current level of scientific Wijnhoven et al. (2009) concluded that the number knowledge of nanosilver, Aitken et al. (2009) stated of well-controlled studies on the potential toxicities that there is: of nanosilver as well as current knowledge of the kinetics of nanosilver is too limited to provide a …indicative evidence of the harm of silver proper foundation for human risk assessment. nanoparticles at low concentrations on aquatic invertebrates, which suggests that the With regard to environmental organisms, concerns environmental release of silver nanoparticles have been raised by the expected increased will be detrimental for the environment emissions and toxicity of nanoscale materials and that any industry/institute using silver compared to bulk forms of the same material. In nanoparticles should consider taking the this respect, silver nanoparticles may serve as an necessary steps to reduce or eliminate the example since the substance is being used in an potential exposure of the environment to these increasing number of consumer products because nanoparticles. of its antibacterial properties. Silver is known to be ecotoxic. However the toxicity is highly dependent The authors further stated that there is insufficient on the form and speciation of the metal. In the evidence to make a risk assessment feasible for registration of silver under REACH (Registration, nanosilver. They did however go on to state … Evaluation and Authorisation of CHemicals) there is sufficient evidence to suggest that silver (Regulation (EC) No 1907/2006), predicted nanoparticles may be harmful to the environment no‑effect concentrations (PNECs) are reported and therefore the use of the as 0.04 µg/L (micrograms per litre) (freshwater), should be considered in this case (Aitken et al., 0.86 mg/L (marine water) and 0.025 mg/L (sewage 2009). treatment plants) (ECHA, 2011). Toxicity tests using silver nanoparticles also reveal very-low‑effect Although preliminary, these studies on the

concentrations. For freshwater algae EC50-values nanoforms of TiO2 and silver as well as carbon as low as 4 µg/L have been found, and values far nanotubes are indicative of wider concerns that below 1 mg/L have been reported for crustaceans materials intentionally designed and engineered (Navarro et al., 2008; Griffitt et al., 2008). EC50 at the nanoscale to exhibit novel properties may is the maximum concentration that induces a also pose emergent risks. They therefore arguably response halfway. Inhibition of nitrifying trigger indicators of early warnings regarding the can occur at concentrations below 1 mg/L (Hu, 2010) potential impacts of engineered nanomaterials, and and the function of wastewater treatment plants as a consequence have led to increased attention and may therefore be affected by the presence of funding on various aspects of nanotechnological silver nanoparticles. For ionic silver it is known health and environmental risks (Hankin et al., 2011; that the speciation in aqueous media determines Aitken et al., 2011; National Academy of Sciences, bioavailability and toxicity. This is likely also to 2012).

536 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

22.5 Current (lack of nano-specific) this system differentiates chemicals on the basis of regulation for nanomaterials their novel molecular structure and not their size. Silver, for example, is an existing chemical under the Whereas there has been some government funding TSCA with its own unique CAS number. The TSCA of environmental, health and safety research into Inventory is not able to differentiate nanosilver the potential adverse effect of nanotechnology and from bulk silver under the current framework, as nanomaterials, there has been limited action from the nanoscale and bulk versions of the substances regulatory decision-makers towards changing both have the same CAS number. This approach existing technology-neutral regulation to take the ignores evidence that size and shape often lead to unique properties of these materials into account. nanomaterials behaving in substantially different This is not surprising given the current state of ways from their bulk counterparts. In the case scientific understanding of nanomaterial hazards of nano-silver, this failure to trigger regulatory and risks. Nor is this lag in regulatory response oversight for the nanoscale substance has already unique to nanotechnologies. As observed by Ludlow raised considerable debate among various et al. (2009), the emergence of a new technology is, stakeholders, including those within the scientific for example, likely to be perceived as a period of community, due to its increasingly widespread use under-regulation in which the development of a in consumer products (see, for example, Chen and specific regulatory response will occur subsequent to Schluesener, 2008; Wijnhoven et al., 2009). an initial period of research and development (R&D) and commercialisation. It must also be remembered It is important, however, to note that the approach that the regulatory frameworks under which adopted under the TSCA is not unique, with chemical nanomaterials currently fall are in any case not substances traditionally regulated on the basis of perfect, with many current regimes outdated and being existing or new based on their CAS number needing to be overhauled. Such recasts were needed in most jurisdictions. At this stage, the majority of prior to the commercialisation of nanotechnology nanoscale substances are considered to be existing and in many respects nanomaterials highlight many chemical substances under these frameworks. of the deficiencies that have existed for some time. One approach that the EPA has implemented in In an effort to elicit information regarding the types order to gather additional data on existing chemicals of nanomaterials being produced and imported into manufactured at the nansocale is through the use of their jurisdictions, some governments, for example its significant new use rule (SNUR). As explained by in the United Kingdom, USA and Australia, have Widmer and Maili (2010), Section 5(a)(2) of the TSCA implemented voluntary reporting schemes for provides the EPA with the regulatory authority to nanomaterials (see, for example, DEFRA, 2006a request addition information on existing chemicals and 2006b; US EPA, 2007; Weiss, 2005; NICNAS, for the purpose of regulatory review where the 2008). Voluntary in nature, and somewhat onerous proposed use of the chemical has significantly in operation, the schemes can be described as at changed since it was initially reviewed. This best underwhelming. In the United Kingdom, regulatory tool has so far been employed for several for example, the Department for Environment, types of nanomaterials, including single-walled and Food and Rural Affairs (DEFRA) received a total multi-walled CNTs. The EPA has proposed a more of 13 submissions over the life of the programme encompassing SNUR that would require companies (2 years). The US scheme, which ended in 2009, that intend to manufacture, import or process new fared a little better with the Environmental nanoscale materials based on chemical substances Protection Agency (EPA) receiving submissions from listed on the TSCA Inventory to submit a significant a total of 31 organisations (DEFRA, 2008; Hansen, new use notice (SNUN) to the EPA at least 90 days in 2009; Maynard and Rejeski, 2009). Given the lack advance (Matus et al., 2011). of buy-in from stakeholders, it is not surprising that other jurisdictions, including France and Even if a nanomaterial has a novel molecular California, have focused their efforts on mandatory structure, the US EPA must show that it may nanomaterial reporting schemes. pose an unreasonable risk of significant exposure before manufacturers are required to undertake Nanomaterials which are defined as chemical environmental, health and safety testing. These substances are regulated by the EPA under the Toxic are just the data the agency needs to determine Substances Control Act (TSCA) (US EPA, 2009a; whether the substance poses an unreasonable risk Breggin et al., 2009). Pursuant to the TSCA, chemical — a classic regulatory paradox. Nonetheless, the substances are typically regulated on the basis of EPA has proposed a data collection rule that would their Chemical Abstract Service (CAS) number; require the submission of certain existing data

Late lessons from early warnings: science, precaution, innovation 537 Emerging issues | Nanotechnology — early lessons from early warnings

on nanomaterials, including production volume, respect, REACH applies uniformly to existing methods of manufacture and processing, exposure and new chemicals, thus overcoming some of the and release information, and available health and difficulties associated with systems analogous to the safety data. Despite these limitations and some TSCA. recent moves towards reform of the TSCA, actual amendments have yet to be implemented (Davies, As with the US system, however, REACH relies on 2006 and 2009; US EPA, 2009b; Breggin et al., 2009). the CAS identification system for the registration A December 2011, EPA Office of the Inspector of chemical substances. One of the limitations of General report (EPA OIG, 2011) found several REACH yet to be addressed is related to whether limitations in the EPAs evaluation and management a nano-equivalent of a substance with different of engineered nanomaterials, including: physico-chemical and (eco)toxicological properties from the bulk substance would be considered as the • Program offices do not have a formal process to same or different from the bulk substance under coordinate the dissemination and utilisation of REACH. The regulation requires that a registration the potentially mandated information; dossier be submitted to the European Chemical Agency containing information about manufacture • EPA is not communicating an overall message to and uses, classification and labelling, and guidance external stakeholders regarding policy changes for safe use. If a nanomaterial is considered to and the risks of nanomaterials; be different from its bulk equivalent, hazard information has to be generated for this registration • EPA proposes to regulate nanomaterials dossier if more than 1 tonne/year is produced. On as chemicals and its success in managing the other hand, if the nanomaterial is considered nanomaterials will be linked to the existing to be the same as a registered bulk material, the limitations of those applicable statutes; appropriateness of the hazard information data submitted in the registration dossier is open to • EPAs management of nanomaterials is limited discussion (Chaundry et al., 2006; Breggin et al., by lack of risk information and reliance on 2009; Milieu and RPA, 2009). To date, the only industry-submitted data. amendment has been to annul the exemption status of carbon and graphite under REACH (CEC, 2008a; The Office of the Inspector General concluded that: Breggin et al., 2009; Milieu and RPA, 2009).

'these issues present significant barriers to It has recently been reported that companies effective nanomaterial management when have set up two different data-gathering groups combined with existing resource challenges. on carbon nanotubes — one group of companies If EPA does not improve its internal processes considers them as new substances while the other, and develop a clear and consistent stakeholder including global chemical producing companies process, the Agency will not such as Arkema and Bayer, consider them as bulk be able to assure that it is effectively managing graphite (Milmo, 2009). This example shows that nanomaterial risks.' whether nanomaterials are to be considered new or not is not just a theoretical question, but a source The EUs approach towards ensuring adequate of confusion among regulated parties. Clearer protection of human health and the environment guidance is expected on the issue from the European also relies heavily on chemical legislation, in Commission as a result of the review of REACH in particular the REACH Regulation, which was 2012. adopted by the Council and Parliament in 2006 and has been implemented progressively within the If nanomaterials are considered to be different from EU since 2007 (EP and CEU, 2006). As articulated in their bulk counterpart, and if they are produced Article 1 of REACH, the purpose of the scheme is or imported in quantities of more than 10 tonnes, to ensure a high level of protection of human health companies have to complete a chemical safety and the environment. To fulfil this overarching assessment. Companies are urged to use existing objective, the regulation has expressly incorporated guidelines, however both the Commission of the the precautionary principle into its text and sets out European Communities (CEC, 2008a) and SCENIHR a no data, no market requirement under Article 5. (2007) and others have pointed out that current Pursuant to this Article, REACH prohibits the test guidelines that support REACH are based on manufacture or sale of any substance in the EU that conventional methodologies for assessing chemical has not been registered with the European Chemical risks and may not be appropriate for assessing risks Agency in accordance with the regulation. In this associated with nanomaterials. This means that,

538 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

although manufacturers and importers might be as sunscreens and moisturisers, while it has been required to provide a chemical safety assessment, reported that fullerenes have been used in a small they cannot rely on the toxicological profile of the number of facial creams (PEN, 2011). equivalent bulk material and cannot use existing test and risk assessment guidelines since these might Although the recast of the Cosmetic Regulation not provide any meaningful results or be practically could be interpreted as a successful political effort to applicable, because of the limitations of conventional address the potential risk and transparency concerns methods (Hansen, 2009; Milmo, 2009). relating to the use of nanomaterials in such consumer products, recent controversies surrounding the Pursuant to the text of the regulation, REACH is recast of the EU Novel Foods Regulation is evidence to be reviewed in 2012. It is generally expected of the challenges that lie ahead for implementing that the revisions will include provisions related future nano-specific revisions to existing legislation to nanomaterials. This is not surprising given such as REACH. In regard to the EU Novel Foods the last-minute attempts to specifically include Regulation, the European Parliament and the nanomaterials in the text of REACH during the Council of the European Union recently failed to second reading speech in 2006 (Bowman and reach an agreement about changes to the instrument van Calster, 2007). However, how REACH can be that would have ensured that the regulation modified to expressly regulate nanomaterials — and includes foods modified by new production the extent thereof — is still up for debate among processes such as nanotechnology. politicians, regulators and stakeholders in the EU. In its current form, the EU Novel Foods Regulation Expressly differentiating nanomaterials from their requires pre‑market approval of all new food bulk equivalents in legislation is not new to the ingredients and products as well as safety European Parliament and Council, as highlighted assessments by European Food Safety Authorities by the recent recast of the regulatory regime for on the composition, nutritional value, metabolism, cosmetics. While this recast was not initiated in intended use and level of microbiological and response to the increasing use of nanomaterials chemical contaminants. Studies on the toxicology, in cosmetic products — but rather to increase allergenicity and details of the manufacturing transparency and streamline human safety process may also be considered. Had the proposed requirements — considerable debate centred on the revisions been adopted, such information relating issue of nanomaterials (Bowman et al., 2010). to nanomaterials might have assisted in addressing current concerns surrounding their use in such The Cosmetic Regulation, adopted in 2009, requires applications in relation to nanoparticles (CEC, that all cosmetics that contain nanomaterials — 2008b; Chaudhry et al., 2012). which are defined as an insoluble or bio-persistent and intentionally manufactured material with one or The failure of the political parties to reach more external dimensions, or an internal structure, a compromise in regard to the Novel Foods on the scale from 1 to 100 nm (Article 2(k)) — be Regulation should act as a warning sign of what to labelled. This will be done by placing the word expect in regard to the likely negotiations around nano in brackets after the nanoscale ingredient revisions to REACH, in which the stakes appear to (Article 19(1)(g)) and will come into effect in 2012. be significantly higher for many parties. There is, we As observed by Bowman et al. (2010), the regulation would argue, the potential for nanomaterials to be does not set a minimum threshold for this labelling overlooked in the 2012 REACH revision discussion, requirement, which suggests that the mere presence with attention focusing instead on the myriad of of any nanoparticles in the cosmetic will be enough other issues in play, including increasing dossier to trigger this requirement. quality, limiting registration bureaucracy and lessening the impact of the regulation on small to In addition to the labelling requirements, producers medium enterprises. will have to provide a safety assessment of the nanomaterial used (European Parliament, 2009). The Many of these issues are so controversial that the regulation also requires the European Commission EU Commission is trying to downplay expectations to create a publicly available catalogue of all for the 2012 REACH revision, arguing that no nanomaterials used in cosmetic products placed fundamental overhaul should be expected (EurActiv, on the market … and the reasonably foreseeable 2011). In regard to nanomaterials, such efforts to exposure conditions (Article 16(10)(a)). Titanium maintain the status quo are worrying given the dioxide, zinc oxide and -based nanocapsules rapidly increasing evidence of risks as well as the are examples of materials used in cosmetics such swift growth of production and commercialisation

Late lessons from early warnings: science, precaution, innovation 539 Emerging issues | Nanotechnology — early lessons from early warnings

of nanomaterials and products. Such political size fits all policy‑based definition has the potential statements are further worrying given the fact that to sideline the science and may fail to capture what the next formal REACH revision with relevance is important for addressing risk. Others within for nanomaterials is not scheduled before 2019 the scientific community have similarly expressed (EP and CEU, 2006). Substantial time is being wasted concern about the fact that the definition fails and effective regulation of nanomaterials is being to take into account the key physico-chemical pushed even further into the future although it is characteristics associated with potential risks clear that immediate revisions are needed to address (see, for example, ChemSec, 2011). In response to the most obvious and short-term limitations of the such criticisms, Hermann Stamm of the European current legislative framework. Commission Joint Research Centre Institute for Health and Consumer Protection has contended Against this background of legislative reform and …such a definition is urgently needed, especially associated debates, a number of other policy-related for particulate nanomaterials. The aim should be activities have occurred within the EU that have the to identify a general class of materials for attention potential to impact on the longer-term regulatory — whether they are benign or hazardous (Stamm, approach in relation to nanomaterials. For example, 2011). It would seem that both camps have valid in 2009 the European Parliaments Environment points; it is important that the crafting of such a Committee adopted a report on regulation of definition does not act as a barrier to the effective nanomaterials in general which calls for application regulation of nanomaterials. of the no data, no market principle (as already incorporated in REACH) until safety assessments The fact that existing legislation may have can be made (Schylter, 2009). While the fate of the serious shortcomings when it comes to effectively proposal to implement this principle is unclear, it regulating nanomaterials is not a new revelation. would appear to put additional pressure on the Government and independent reviews of European Commission and the Council to address the current regulatory frameworks and their the potential risks of nanomaterials in the short to applicability to nanotechnologies have now been medium term. published (see, for example, Chaudhry et al., 2006; Ludlow et al., 2007; European Commission, Of arguably greater significance is the October 2008). While the reports have varied in scope, 2011 recommendation of a definition of the term method and the instruments that they have nanomaterial by the European Commission sought to evaluate, each has concluded that specifically for legislative, policy and research nanomaterials are currently captured under the purposes. As set out in the Official Journal of the existing regimes. However, the failure of such European Union (2011), a nanomaterial means: instruments to differentiate between nano-based products and their conventional counterparts '… a natural, incidental or manufactured has raised a number of concerns regarding the material containing particles, in an unbound ongoing effectiveness of these regimes. A number state or as an or as an agglomerate of cross‑cutting issues that appear to be common and where, for 50 % or more of the particles to most jurisdictions have now been examined in the number size distribution, one or more through these reviews. The main areas of concern external dimensions is in the size range include that, as discussed above, the regimes do not 1 nm‑100 nm. differentiate between novel and known substances for the purposes of triggering regulatory oversight; In specific cases and where warranted by that requirements for regulators to undertake concerns for the environment, health, safety or safety evaluations on novel substances are competitiveness the number size distribution triggered by mass or volume thresholds that are threshold of 50 % may be replaced by a not tailored to the current production volumes threshold between 1 and 50 %.' of nanoscale materials; the lack of trust in the appropriateness of conventional risk assessment This definition differs considerably from the protocols and technical guidelines; and that risk one in the Cosmetic Regulation (as articulated thresholds and exposure limits established with above) and was mooted in relation to the recast existing methodologies are questionable (Ludlow of the Novel Foods Regulation. It is therefore et al., 2007; Baun et al., 2009). not surprising that this recommendation for a definition has not been without considerable In most countries, nanomaterials are still being controversy and global debate. According to treated within existing regulatory frameworks, Maynard (2011), the Commissions push for a one under which the nanomaterials have inherited

540 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

the scope and features of the previous analogous Another issue that makes engineered nanomaterials, regime (Stokes and Bowman, 2012). At this stage especially nanoparticles, different from conventional of development and commercialisation, countries industrial chemicals is their ability to agglomerate such as the US, Australia, China and India, as well (form clusters of weakly bound particles) or as the Organisation for Economic Co-operation and aggregate (form clusters of strongly bound particles) Development (OECD) and the EU, are proposing into stable particles. Aggregated particles are to treat nanomaterials primarily in the same generally considered to be less prone to biological manner as their conventional chemical counterparts uptake, however it is not correct to assume that (CEC, 2008; US EPA, 2007 and 2009b; OECD, 2009a they are inherently safe. While the aggregation and 2009b). In doing so, they have opted to retain and agglomeration behaviour of engineered the regulatory status quo despite the growing body nanoparticles is only partly understood, it is known of literature that suggests that some nanomaterials that their formation is concentration-dependent may cause harm to human and/or environmental and that smaller aggregates/agglomerates may health. This approach is not surprising given the be formed at lower initial concentrations. If current knowledge deficits in the evolving state toxicity is inversely associated with aggregation/ of the scientific art and a general lack of express agglomeration size, our traditional understanding of reliance on the precautionary principle in most concentration‑response relationships may have to be jurisdictions. altered for nanoparticles since higher concentrations may not necessarily result in higher toxicity. Australia is one country that has explicitly moved Furthermore, it is not known whether larger benign to differentiate the requirements for some new agglomerates may be broken down after inhalation industrial nanoscale chemicals. Recent administrative or ingestion, resulting in smaller, and perhaps changes to its National Industrial Chemicals less benign, agglomerates or single particles. For Notification and Assessment Scheme (NICNAS) these reasons the statement that lower exposure (which may be considered analogous to the TSCA), equals lower effects should be seriously scrutinised which came into effect in January 2011, have sought before it can be considered valid for engineered to remove several of the low-volume/low-concentrate nanoparticles (Baun and Hansen, 2008; Baun et al., exemptions that usually apply to new industrial 2009). chemicals (NICNAS, 2010). While minor and incremental in nature, such a shift is indicative of how In environmental hazard identification it is not some countries may attempt to tweak their regulatory only the toxicity, but also the degradability and frameworks in the first instance rather than move potential for bioaccumulation that are used as towards more wholesale changes. parameters to identify chemical compounds that are environmentally hazardous. Very few studies A number of features related to engineered have addressed these two parameters for engineered nanomaterials indicate that the identification of nanomaterials (Stone et al., 2010; Mikkelsen et al., hazards may deviate from what is known about 2011) and, as described above, serious concerns regular chemicals. While our current approach have been raised about whether the knowledge to toxicity-driven risk is based on the paradigm built up for regular chemicals can be transferred attributed to Parcelsus, that it is the dose that makes to nanoparticles. This led the SCENIHR (2007) to the poison, and most extrapolations from toxicity conclude that: The criteria used for persistence, tests assume that there is a correlation between mass bioaccumulation and toxicity (PBT) assessment and toxicity, this may not hold true for engineered applied for substances in soluble form should be nanoparticles (Baun and Hansen, 2008). As pointed assessed for applicability to nanoparticles. out in a number of studies, other properties such as surface area and surface chemistry may be better Finally, in order to take the unique properties of any indicators of the toxicity of some nanoparticles. This type of nanoparticles into consideration, it has often raises the question of how to determine the relevant been argued that risk assessments of nanoparticles exposure concentrations in laboratory studies and need to be completed on a case‑by‑case basis in occupational and environmental settings. In (see for example, SCENIHR, 2007 and 2009; Stone response to this concern, SCENIHR has stated that et al., 2010). Past experiences with case-by-case amendments have to be made to the existing technical risk assessment of regular chemicals indicates guideline for risk assessment of chemicals since: due that such an approach can be very time- and to the physico-chemical properties of nanoparticles, resource‑intensive even with well-defined data their behaviour and their potential adverse effects demands and hence one has to wonder whether are not solely dependent on exposure in terms of the this is the most appropriate approach when it mass concentration … (SCENIHR, 2007). comes to risk assessment of nanoparticles. The

Late lessons from early warnings: science, precaution, innovation 541 Emerging issues | Nanotechnology — early lessons from early warnings

situation for these is further complicated by the fact cases where the discussion of the associated risks that the hazard characteristics will be linked not has followed the development of new technologies, only to the chemical identity but also to a number the discussion on the proper regulatory framework of other characteristics and their combinations. For for the governance of nanotechnology risks is example, it has been claimed that there are up to accompanying the development of the technology 50 000 potential combinations of single‑walled carbon and the associated products themselves. While nanotubes (SWCNTs), depending on their structural hard government action may still be limited, we type, length, surface coating, manufacturing have however seen the emergence of a number processes and purification method (Schmidt, 2007). of nano‑specific self‑regulatory activities within Each of these 50 000 SWCNTs may have different industry, including codes of conduct, guidance chemical, physical and biological properties that documents and risk assessment/management determine their overall hazard. Although not all of frameworks (Bowman and Hodge, 2009; Meili and them are expected to be of commercial relevance, Widmer, 2010). Voluntary in nature, they sit within there are many kinds of nanoparticles, such as the shadow of formal regulatory obligations and do fullerenes, quantum dots, and metal and metal not seek to usurp legislative requirements. oxide nanoparticles, which imply a great complexity in performing case-by-case risk assessments for Currently, most economies investing in nanoparticles. nanotechnology season discussions about future directions in research with questions concerning potential risks and how to manage them. Yet despite 22.6 Late lessons from early warnings some moves (for example, the funding of early for nanotechnology investigations into environmental, health and safety risks) to respond to ignorance and uncertainty rather A comparison between the EEA recommendations than simply discuss them, coordinated action seems made in 2001 and the current situation for slow to emerge. The EEA report recommends looking nanotechnology shows that stakeholders are doing out for warning signs such as materials that are novel, some things right, but we are still in danger of bio-persistent, readily dispersed or bioaccumulative, repeating old, and potentially costly, mistakes. In this and/or materials that lead to irreversible action section we briefly discuss the current development (such as mesothelioma caused by the inhalation of of regulation and environmental, health and safety asbestiform fibres). research in view of the late lessons from early warnings learned by the EEA in 2001. These warning signs are clearly relevant to many nanomaterials, some of which have novel properties, may be capable of being incorporated in highly 22.6.1 Lessons 1–3: heed the 'warnings' diverse products, may be transported to places in the human body in new ways, such as across the , According to Late lessons from early warning Volume 1. brain or placental barriers, and may be designed to 'No matter how sophisticated knowledge is, it will be persistent. Too little is known at this early stage always be subject to some degree of ignorance of the technologys development trajectory to predict (i.e. inevitable surprises, or unpredicted effects). To the environmental fate of many nanomaterials, be alert to — and humble about — the potential gaps and appropriate documentation of environmental in those bodies of knowledge that are included in our dispersion through is not expected in the decision-making is fundamental' (EEA, 2001). short term (SCENIHR, 2007). The extent to which specific nanomaterials are bioaccumulative or lead Perhaps more than any preceding technology, the to irreversible impact is largely unknown, but the early development of nanotechnology has been current state of knowledge suggest that the potential characterised by discussions of potential risks and exists for such behaviour under some circumstances the need for regulatory reform (Grieger et al., 2009; (Moore, 2006; Stone et al., 2011; Mikkelsen et al., 2011) Fiedler and Reynolds, 1994). Such discussions have (see Box 22.1 on how EEAs warning signs apply to always been an integral part of the government-led C60 and CNTs). National Nanotechnology Initiative (NNI) in the US, for example, while in the EU the landmark report The global response to these warning signs may published by the Royal Society & Royal Academy of be described, at least in our view, as patchy at best, Engineering (RS and RAE) in 2004 emphasised the with governments being slow, and sometimes need to address uncertainties regarding the risks of complacent, regarding the need to gather essential nanomaterials (RS and RAE, 2004). Levi-Faur and data, for example on production, use patterns and the Comhanester (2007) have observed that unlike other effectiveness of current types of personal protection

542 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

equipment (see Section 22.5 on the current regulation testing procedures and equipment, how to assess of nanomaterials). Saying this, it is important to human and environmental effects, and how to acknowledge that efforts to date have been better do exposure assessments and characterisation of than those seen in response to the emergence of nanomaterials) should be relatively easy to develop, earlier technologies, but they are still far from ideal. as the critical questions to be addressed are generally agreed (Maynard et al., 2006; Grieger et al., 2009). A number of reports have made specific But the EEA report highlights the dangers of entirely recommendations on developing responsive research missing important areas because the right questions strategies (see for instance Oberdorster et al., 2005b; have not been identified, leading to blind spots in Maynard et al., 2006; Tsuji et al., 2006; SCENIHR, our understanding. The report cites the widespread 2006; National Academy of Sciences, 2012). For use of anti-microbials as growth promoters in example Maynard et al. (2006) called for: food animals, methyl tert-butyl ether (MTBE) and tributyltin as three examples where conventional • the development of strategic programmes that thinking led to inappropriate assumptions and a enable relevant risk-focused research, within the lack of recognition of broader issues. At present it is next 12 months; not clear whether the recognition of ignorance in the field of nanomaterial‑related EHS risks is sufficient • the development of instruments to assess to avoid blind spots, or whether the novel properties exposure to engineered nanomaterials, within the of nanomaterials inherently will generate blind spots next 3–10 years; because of their novelty (see Box 22.1).

• the development of robust systems for evaluating the health and environmental impact of 22.6.2 Lessons 4 and 11: reduce obstacles to action engineered nanomaterials over their entire life, within the next 5 years; Even when research throws up useful information, it may be ignored and overlooked through what the • the development and validation of methods to EEA authors call institutional ignorance. They cite evaluate the toxicity of engineered nanomaterials, cases where regulators have made inappropriate within the next 5–15 years; appraisals because of the blinkers imposed by their specific disciplines — such as the preoccupation of • the development of models for predicting the medical clinicians with acute effects when dealing potential impact of engineered nanomaterials on with radiation and asbestos. There is a real danger the environment and human health, within the of similar errors being made with nanotechnology, next 10 years. which crosses many fields of expertise. One needs to draw on physics, chemistry, computer sciences, Calls for research proposals in the European seventh health, environmental sciences and law to understand framework programme reflect some of these nanomaterial properties and risks (Karn et al., recommendations, and a number of countries are 2003). A number of multidisciplinary centres for beginning to develop integrated environment, health nanoscience and nanomanufacturing have been and safety (EHS) research programmes, such as the established around the world, but only a few of cross-agency risk-research strategy published by the these address health, environmental and social NNI (2008). However, there are still critical gaps in aspects. It is critical to set aside resources to create our knowledge that need to be addressed in EHS an infrastructure that gets people working together research programmes. These include, but are not across disciplines (Lynch, 2006). limited to, epidemiological investigation of exposed populations; the behaviour and impact of ingested Interdisciplinary obstacles also affect regulatory nanomaterials; investigation of the fate, behaviour oversight in decision-making (EEA, 2001). In a and (eco)toxicity of nanomaterials throughout the discussion on how nanomaterials were covered under life cycle; and interactions between nanomaterials the TSCA, the US EPA appeared to be constrained and environmental matrices such as natural organic by a world-view rooted in chemistry, stating that the matter and sediments and other pollutants already sole factor that determines whether a nanomaterial is present in the environment (Maynard 2006; Baun legally classified as new depends on whether it has a et al., 2008; Grieger et al., 2009; National Academy of unique molecular identity (US EPA, 2007). However, Sciences, 2012). it is now clear that characteristics other than molecular identity — such as particle size and shape Research strategies that target recognised areas of — can affect exposure and response to engineered uncertainty (including the applicability of current nanomaterials (SCENIHR, 2007).

Late lessons from early warnings: science, precaution, innovation 543 Emerging issues | Nanotechnology — early lessons from early warnings

Box 22.1 EEA's warning signs applied to fullerenes and carbon nanotubes

To acknowledge and respond to ignorance, i.e. potential risks that you do not know (EEA, 2001), seems almost impossible when it comes to a rapidly emerging technology such as nanotechnology. In cases of ignorance, the EEA recommends being proactive, alert and humble about the state of the scientific evidence indicating harm as well as looking for warning signs such as novelty, persistence, ready dispersion, bioaccumulation, leading to potentially irreversible action. These lessons bear an uncanny resemblance to many of the concerns now being raised about various forms of nanomaterials such as the two types of nanoparticles: C60-fullerenes and carbon nanotubes (CNTs).

No single exhaustive taxonomy exists for novel materials and, as noted by the Royal Commission on Environmental Pollution (RCEP, 2008), it is unlikely that one is possible or even necessarily desirable. That said, one could argue that nanomaterials are novel by definition in the sense that many of the definitions of nanotechnology require either novel applications, whatever they might be, and/or that nanomaterials exhibit novel properties compared to bulk materials (see for example the definitions cited earlier in the chapter). In the following, C60 and CNT will be used as illustrative examples of nanomaterials that are novel in their use pattern and properties.

At present, very few studies have addressed the degradability of engineered C60 and CNT, but, because of their structure, they are expected to be persistent in the environment. Both C60 and CNT are often seen as anthropogenic, however they may also be formed in forest fires or volcanic eruptions. Although the sources of naturally occurring carbon-containing nanoparticles are different from the engineered ones, the particles are, from a chemical point of view, identical, and geological studies have shown that both C60 and CNT may be very resistant to degradation. Thus, Becker et al. (1994) observed C60 in 1.85 billion year-old shock-produced breccias of the Sudbury impact structure in Ontario, Canada and C60 has also been found in a 70 million-year-old fossil dinosaur eggshell from Xixia, China (Zhenxia et al., 1998). CNT and fullerenes have been extracted from 10 000-year-old ice-core melt samples (Murr et al., 2004).

Whether C60 and CNT are readily dispersed depends on a number of factors such as the environmental compartment considered (e.g. air, water, soil). Little is known about the fate and transport of C60 and CNT in air and soil, but under laboratory conditions hydrophobic nanoparticles such as C60 and CNT have been found to aggregate rapidly (Fortner et al., 2005; Baun et al., 2008). As a result of sedimentation, they may therefore not be readily dispersed after emission to the aquatic environment. However, the dispersivity of nanomaterials can be altered, for example by changing the surface chemistry, and hydroxylated C60, for example, is much more soluble in water (Sayes et al., 2004). What happens in the environment, and how interaction with natural substances (e.g. humic substances) and water-living organisms influence dispersion, are however unclear (Roberts et al., 2007; Hansen et al., 2009).

The potential bioaccumulation of nanomaterials is believed to depend on a combination of the specific properties of the nanomaterial (such as biodegradability, lipophilicity, aqueous ) that influence overall bioavailability. For example carbon nanotubes are known to be non-biodegradable, insoluble in water and lipophilic, which indicates that carbon nanotubes have a potential to bioaccumulate. However, there is a profound lack of studies addressing the issue of bioaccumulation of engineered nanomaterials (RCEP, 2008).

Because of the lack of scientific research, it is currently almost impossible to say whether or not the production and use of nanomaterials could lead to potentially irreversible action. Some studies have indicated that some CNTs might be able to cause effects that would be classified as irreversible (e.g. Poland et al., 2009; Smith et al., 2007). Widespread production and use of C60 and CNT will inevitably lead to the release of these materials into the environment, and hence an irreversible action, as they would be practically impossible to locate and recover after release (Hansen et al., 2009).

22.6.3 Lessons 5 and 8: stay in the real world nanomaterial company expecting to see a high-tech work environment. Instead, he found the future The EEA panel assertion from 2001 (EEA, 2001) that looked a lot like the past with men in grease-stained it is often assumed that technologies will perform to blue coats […] story-tall spray-drying machines […] the specified standards. Yet real life practices can be noisy milling operations and workers with face masks far from ideal echoes claims made of nanotechnology. covered by a pale dust stemming from emptying In 2006, Rick Weiss of the Washington Post visited a buckets of freshly made powders (Weiss, 2006).

544 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

It is often assumed that nanotechnology will be It is generally difficult to evaluate whether conducted with small quantities of material, within proclaimed pros and cons are valid both in sealed processes. Reality can be very different the short and the long term. However, the and the past tells us that persistent substances process of determining more likely scenarios is used in closed settings or incorporated in solid vital to the future development of sustainable matrices (like PCBs) will eventually end up in nanotechnologies. As we emerge from the first the environment. Moreover, there is evidence flush of nano‑enthusiasm and begin the hard work that the R&D community is entrenched in the of translating good ideas into viable products, this philosophy that basic research will ultimately is a lesson that is more relevant than ever if an solve real-world problems through a one-way appropriate balance between benefits and risks is to process of knowledge , and that they do be struck (Maynard et al., 2011). not need to worry about EHS issues. A study by Powell (2007) found that many scientists who are If proclaimed pros do not materialise in the developing new nanotechnologies do not think foreseeable future despite heavy public investments, that nanotechnologies pose new or substantial risks or if projected cons are not investigated, but later and that concerns about risks are based on invalid prove to be significant, decision-making processes science (Powell 2007). This is a mistake in our view, will be undermined, and public trust may be and there is plenty of historical evidence to support compromised. this view in the first EEA report Late lessons from early warnings (EEA, 2001), including the sorry tale A key feature of the public reaction to the emerging of asbestos. Clearly, applied researchers and the evidence for bovine spongiform encephalopathy EHS community need to be involved in informing (BSE) in the late 1980s was the surprised revulsion policy decisions. According to the EEA, this includes that cows and other ruminants were being fed on making use of the information that workers and offal and bodily wastes. The EEA panel in 2001 users can bring to the regulatory appraisal process, speculates that accounting for wider social values although such knowledge of course needs as much at an earlier stage might have limited the scale of critical appraisal as specialist knowledge. BSE problems. The extent to which societal interests and values can prevent real risks with emerging Nanotechnology is complex, and it can be argued technologies is debatable. Yet these interests and that non-experts have little to contribute to its safe values influence what is considered acceptable, development and use currently. But non-specialists and consequently what is accepted or rejected. intimately involved with a technology can bring Nanotechnology is proclaimed to have a tremendous unique insight to the table since they may have some potential to address major global challenges like of the clearest ideas about what is important, what , and provision of clean has the potential to work and what may not (Gavelin water. Yet precisely because of the widespread et al., 2007). applications of nanotechnology, citizens around the world are as much stakeholders in the technology as the governments, industries and scientists 22.6.4 Lessons 6 and 9: consider wider issues promoting it. But so far the deliberate engagement of citizens and the public in risk-related decisions on Concerns have often been raised that speculation nanotechnology has been very limited. on risks overshadows real benefits, or that an unbalanced promotion of possible benefits will prevent potential risks from being critically 22.6.5 Lesson 7: evaluate alternative solutions scrutinised. This lesson may simply be summarised by saying, Nanotechnology is in such a position (Maynard dont become so enamoured by a new technology, et al., 2011). Pros include economic benefits, that you are blinded to alternative solutions. improved materials, reduced use of resources and Past lessons have shown there is a tendency new medical treatments (RS and RAE, 2004; Roco for proponents to justify heavy investment in a and Bainbridge, 2005), while cons mainly revolve new technology by promoting its application to around worker health, consumer exposure and every conceivable problem, with the result that environmental impacts. Comparisons have also been alternatives are insufficiently scrutinised, and the made between ultrafine particles in the atmosphere most appropriate solution not always selected. — which are known to cause health problems — and specific types of nanoparticles (RS and RAE, 2004, While nanotechnology is diverse and widely Oberdorster et al., 2005b; Maynard et al., 2006). applicable, this would seem a potential pitfall as

Late lessons from early warnings: science, precaution, innovation 545 Emerging issues | Nanotechnology — early lessons from early warnings

the number of nanoscale solutions looking for a according to the EEA panel one factor in the slow problem continues to grow. And with international UK response to BSE was that the governmental nano-fever running high, everyone wants to be at regulatory body was responsible first to the industry the forefront of the nanotechnology revolution. and only second to consumers. In many countries, In many cases, nanotechnology will provide the the organisations responsible for overseeing the means to overcome challenges — but the lesson to development of nanotechnologies through R&D are be learnt is the need to find the best solution to a the very ones that address health and environmental given problem, rather than to squeeze a solution out issues. of the latest technology. This means that, in some cases, while nanotechnology could be used, it may In testimony to the US Congress House Committee be questionable whether it should. In the context of on Science and Technology, Richard Dennison of such discussions, assessment of alternatives can be the Environmental Defense Fund, a non-profit used to provide helpful guidance in case of doubt environmental campaign group, wrote that: as it provides a structured approach to examining a wide range of alternatives (e.g. technologies, 'we have become convinced that a conflict of processes, social changes) to potentially hazardous interest has arisen from the decision to house activities (Rossi et al., 2006). within NNI the dual functions of both seeking to develop and promote nanotechnology Alternatives assessment is normally a six-step and its applications, while at the same time process that includes: aggressively pursuing the actions needed to identify and mitigate any potential risks that 1) identification of target(s) for action; arise from such applications. That conflict of interest is both slowing and compromising 2) characterisation and prioritisation of end uses; efforts by NNI and its member agencies and departments to effectively address 3) identification of alternatives; nanotechnologys implications' (Denison, 2007a).

4) evaluation and comparison of alternatives; Concerns that such a conflict of interest could jeopardise effective environmental, health and safety 5) selection of preferred alternative(s); and research were most recently articulated by the US National Academies of Science in a research strategy 6) review of selected alternative. for environmental, health and safety aspects of engineered nanomaterials: The scope of any alternatives assessment should be broad enough to examine the service and function 'There is a concern that the dual and potentially that it requires as opposed to just examining, conflicting roles of the NNI — developing for example, the opportunities of substituting a and promoting nanotechnology and its hazardous chemical with a less hazardous one. applications while identifying and mitigating In the case of nanomaterials this means that risks that arise from such applications — alternatives need not simply be nanomaterials, impede implementation and evaluation of but may include the process or administrative the EHS risk research…To implement the changes that reduce the need for the materials research strategy effectively, a clear separation in the first place (Rossi et al., 2006; Linkov et al., of management and budgetary authority and 2009). While alternatives assessment is generally accountability is needed between the functions applied to existing technologies and problems, the of developing and promoting applications of thinking about alternatives can be applied at the nanotechnology and of understanding and design , which did not occur in the case of assessing potential health and environmental nanotechnology. implications. Such a separation is needed to ensure that progress in implementing an effective nanotechnology‑related EHS research 22.6.6 Lesson 10: maintain regulatory independence strategy is not hampered' (National Academy of Sciences, 2012). The EEA panel found evidence in the case studies that interested parties are often able to unduly While an integrated approach to understanding influence regulators. As a result, decisions that the risks and benefits of nanotechnology is might reasonably have been made on the basis of critical, when the promoters of nanotechnology, available evidence were not taken. For example whether government or industry, have a strong

546 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

influence over oversight, independent regulatory 22.7 So have we learnt the lessons? decision‑making becomes compromised. Perhaps more insidiously, research and development Although the EEA panel was writing about decisions end up being influenced by what existing technologies, and some of the 12 lessons will ultimately promote the technology, rather learned are not directly applicable to all emerging than what will protect producers, users and the technologies, many of the lessons are directly environment. relevant to nanotechnology today. Yet the picture is not as bleak as it might be. Table 22.1 provides a qualitative analysis of 10 main EU Member State 22.6.7 Lesson 12: avoid paralysis by analysis national and multilateral scientific reports that have provided input to the EU regulatory and political In the face of uncertainty, a frequent response is to decision-makers on nanomaterials over the course call for more research before action is taken. Yet, as of the last decade. For each of the late lessons from the EEA panel note, Experts have often argued at an the first volume of this publication (EEA, 2001) we early stage that we know enough to take protective have provided an assessment of whether the lessons action (EEA, 2001). Good policy depends on there have been mentioned in passing (+), have identifying the right balance between information been substantially discussed and/or analysed (++), and action while keeping the end-point (preventing or whether a strategy to address a given lesson has harm) in mind, and building in review procedures been suggested (+++). Blanks means that no noticed for course corrections. was taken of these lessons.

Twenty years have elapsed since first indications While progress in developing sustainable of nanomaterial harm were published (Ferin et al., nanotechnologies has been slow, the qualitative 1990; Oberdorster et al., 1990), and in the intervening analysis above indicates that policy makers and time an increasing body of literature has been relevant stakeholders seem to have learnt at least developed on how nanomaterials interact with cells, some of the lessons: they are asking more critical mammals and aquatic organisms (Hansen et al., questions early on about health and environmental 2007; Stone et al., 2010). Yet many governments fate and effects; developing collaborations that still call for more information as a substitute for cross disciplines, departments and international action; there are indications that understanding and boundaries; beginning the process of targeting managing the risks of engineered nanomaterials research to develop relevant knowledge; engaging are being paralysed by analysis. While it is clear stakeholders; and asking whether existing oversight that more scientific information is needed, we need mechanisms are fit for purpose. to act on what we know now, to enable industry to produce and market nanotechnology-enabled But are we doing enough? The second half of products that are as safe as possible. Engineered Table 22.1 provides a qualitative analysis of the main nanomaterials are already on the market, and in EU regulatory actions taken over the course of the some cases the risks are poorly understood and last decade in response to the twelve lessons. may therefore be ineffectively regulated. Applying current knowledge to nanotechnology oversight will The Cosmetic and the Biocides regulations not solve every problem, but it will help prevent acknowledge that there is a high level of basic mistakes being made while the knowledge scientific uncertainty regarding the risks of needed for more effective oversight is developed. nanomaterials. They require industry to submit data and information about physical/chemical One way to facilitate decision-making on characteristics and the exposure and toxicological nanomaterials may be to develop design criteria to profile of a given nanomaterial, thereby providing identify which nanomaterials are of higher or lower some elements of a strategy toward long-term concern because of their intrinsic properties or use environmental and health monitoring to help or exposure characteristics. For example, Maynard identify and reduce scientific blind spots. The et al. (2011) have proposed principles of emergent burden of providing health and safety data being risk, plausibility and impact to identify materials placed on industry also helps to overcome the of high concern. Further, a thorough consideration problem of paralysis by analysis since companies of health and safety implications at the design are in theory not able to market their products phase of a nanomaterial, including consideration of without proper data and information about possible safer production methods and alternatives risks. To some extent, regulatory independence to the material, will facilitate decisions as economic is also ensured in the Cosmetic and the Biocides interests are not fully entrenched at that point. regulations in the sense that the scientific

Late lessons from early warnings: science, precaution, innovation 547 Emerging issues | Nanotechnology — early lessons from early warnings

Table 22.1 Late lessons learned, as indicated in 10 EU Member State nanomaterials reports

Lessons (EEA, 2001)

* and

Royal S& RAE Royal (2004) DG Sanco (2004) Chaundry et al. (2006) IRGB (2006) SCENIHR (2007) RCEP (2008) CEC (2008) Stone et al. (2009) RIVM (2009) et al. Aitken (2009) SCENIHR (2009) Cosmetic Regulation Biocides Regulation Additives Food Regulation RoHS WEEE **

Acknowledge and respond to ++ ++ ++ ++ ++ ++ + ++ ++ ++ ++ ++ ++ + + ignorance, uncertainty and risk in technology appraisal Provide long-term environmental and ++ ++ ++ + ++ + ++ + ++ ++ ++ + + health monitoring and research into early warnings Identify and work to reduce scientifc ++ + + ++ ++ + + ++ ++ ++ + + blind spots and knowledge gaps Identify and reduce interdisciplinary ++ + + + obstacles to learning Account for real-world conditions in + + + + regulatory appraisal Systematically scrutinise claimed + + + + ++ benefts and risks Ensure use of lay knowledge, as well ++ + ++ as specialist expertise Evaluate alternative options for meeting needs, and promote robust, diverse and adaptable technologies Account fully for the assumptions and ++ + ++ + values of different social groups Maintain regulatory independence of + ++ interested parties while retaining an inclusive approach to information and opinion gathering Identify and reduce institutional ++ + + obstacles to learning and action Avoid paralysis by analysis by acting + + + ++ + + + + + to reduce potential harm when there are reasonable grounds for concern

Note: A empty cell indicates no notice taken + mentioned in passing; ++ substantially discussed and/or analysed; +++ strategy suggested/implemented * Restriction of Hazardous Substances Directive; ** Waste Electrical and Electronic Equipment Directive.

committees such as the European Commissions overseen by the very government organisations Scientific Committee on Consumer Safety and the that promote it; research strategies are not leading European Food Safety Agency that are responsible to clear answers to critical questions; collaboration for evaluating the health and safety data and the continues to be hampered by disciplinary and information provided by industry are independent institutional barriers; and stakeholders are not being from the regulatory agencies that promote the use fully engaged, or not being engaged early enough. of nanomaterials in those same products. However, In part this is attributable to bureaucratic inertia, these agencies have recently come under attack although comments from some quarters, such as risk for not being independent from industry interests research jeopardises innovation or regulation is bad (Muilerman and Tweedale, 2011). for business, only cloud the waters when clarity of thought and action are needed. In the of the 14 case studies in the first volume (EEA, 2001), the question here seems not to be If we are to realise the commercial and social whether we have learnt the lessons, but whether benefits of nanotechnology without leaving a we are applying them effectively enough to prevent legacy of harm, and to prevent nanotechnology nanotechnology becoming yet another future case from becoming a lesson in what not to do for future study on how not to introduce a new technology. generations, perhaps it is time to go back to the Despite a good start, it seems that we have become classroom and re‑learn these late lessons from early distracted by the way that nanotechnology is being warnings.

548 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

22.8 Precautionary strategies for technologies, they do represent plausible worst‑case nanomaterials scenarios. Given that the shelf life of specific new nanotechnology products is likely to be short Linkov et al. (2009) have pointed out that there because of continuous technology improvements, seems to be a substantial time lag between the Linkov et al. (2009) argue that the approaches to emergence of products containing nanomaterials, regulating these materials should be adjusted to the the generation of EHS data and their subsequent use evolving nature of the field. The question however is by regulatory agencies (see Figure 22.2). how this should be done.

They argue that this results from these agencies RCEP (2008) has pointed out that existing having limited resources and that it will take time regulatory approaches cannot be relied on to for regulatory agencies to adjust risk assessment detect and manage problems before a novel procedures so that they are applicable to technology such as nanomaterials has become nanomaterials. The precise extent of the time lag is ubiquitous. Although, this observation is rather unclear, but there is historical evidence indicating bleak and discouraging, several precautionary that it will not be less than two decades. In 1977, strategies have nevertheless been suggested over Lawless and his team analysed 45 episodes of public the past decade. Some have focused on providing alarm or strong concern over various technologies recommendations on how to adapt existing including reproduction and genetics, food and legislation, for example Chaundry et al., 2006; Fuhr medicine, and environmental problems. A common et al., 2007; Franco et al., 2007; Ludlow et al., 2007 theme identified by Lawless was that social and Breggin et al., 2009. Specific recommendations institutions grapple with the problem for varying include clarification of key terms and definitions amounts of time while on effects increase of nanotechnology and material properties; in the technical literature. On average, this delay ensuring the relevance of the scope and objectives is one or two decades (Lawless, 1977). Volume 1 of existing legislation; clear definition of thresholds of this publication (EEA, 2001) found that the time relevant to nanomaterials; and risk assessment gap between the first report of harm and effective of nanomaterials prior to or after release into the regulatory action was decades, and in some cases, environment. even over a century. Although the cases analysed by the EEA and Lawless may not reflect all emerging Others have focused on providing recommendations on how to adapt existing risk assessment methods and risk management procedures such as the nano‑risk framework jointly developed by the Figure 22.2 Schematic representation of the American non-governmental organisation emergence of nanotechnology Environmental Defense and the DuPont Corporation products in comparison with (ED and DuPont, 2007). This framework describes generated EHS data a process for ensuring the responsible development of nanoscale materials, and is designed to be used Emergence of nanotechnology products in comparison to generated EHS data iteratively at different stages of development including basic R&D, prototyping, pilot testing, Volume test marketing, and finally when new information Emerging nanoproducts becomes available. The suggested framework consists of six distinct steps:

• develop the nanomaterial and its intended uses; Generated EHA data • develop nanomaterial hazard and exposure profiles along the full life cycle;

Gap • evaluate information generated to assess the probability of nanomaterial risks;

EHS data anylysed • evaluate risk management options and by regulatory recommend a course of action; agencies Time • decide alongside key stakeholders whether to Source: Reprinted with permission from Linkov, I. et al., 2009. continue R&D and production;

Late lessons from early warnings: science, precaution, innovation 549 Emerging issues | Nanotechnology — early lessons from early warnings

• update and re‑execute the risk evaluation ethical issues; stakeholder and public dialogue; regularly and share appropriate information with and ensuring the responsible development of relevant stakeholders (ED and DuPont, 2007). nanotechnologies. Key recommendations include:

A third series of recommendations from various • Research into possible adverse health, safety stakeholders and experts, for example the and environmental impacts of nanomaterials, International Council on Risk Governance (2007) which the RS and RAE (2004) argue should be and RCEP (2009), have a much broader focus an integral part of the innovation and design and have provided recommendations on issues process of products including nanomaterials. more relevant to the governance of emerging technologies and innovation. In addition to a wide • Avoidance of the release of manufactured range of recommendations focused on restructuring nanoparticles and nanotubes into the risk research and regulation of chemicals and environment as far as possible. emerging technologies, RCEP (2009) has called for the development of flexible and resilient forms of • Regulatory authorities to consider whether adaptive management to allow us to handle such existing regulations are appropriate to protect difficult situations and emergent technologies humans and the environment and inclusion of while recognising the high degree of ignorance and future applications of nanotechnologies in their uncertainty and the time it will take to address these. horizon-scanning programmes to ensure timely According to RCEP (2009), key elements of such a identification of any regulatory gaps. framework should be structured around modification and extension of the existing regulatory framework • Consideration of whether ethical and social as a matter of urgency, and development of an early implications of advanced technologies (such warning system including robust arrangements for as nanotechnologies) should form part of the monitoring complemented (and informed) by the full formal training of all research students and staff range of perspectives on innovation. working in these areas.

Similarly, ICRG (2006, 2007) has suggested an • Comprehensive qualitative work involving integrated analytic framework for risk governance, members of the general public as well as consisting of pre‑assessment, risk appraisal, and members of interested sections of society, and judgment of tolerability and acceptability, with risk government funding of public dialogue around management and communication as integrated the development of nanotechnologies. elements that provide connectivity between the other elements. Application of the framework • Establishment of a group that brings together to nanotechnologies has led to a number of representatives of a wide range of stakeholders recommendations that fall into five categories: to look at new and emerging technologies and improve the knowledge base; strengthen risk identify, at the earliest possible stage, areas management structures and processes; promote where potential health, safety, environmental, stakeholder communication and participation; ensure social, ethical and regulatory issues may arise social benefits and acceptance; and collaboration and advise on how these might be addressed. between stakeholders and nations. While a regulatory, stakeholder engagement and Recently, the German Advisory Council on the R&D strategy are critical elements of a precautionary Environment for the German Government has approach to nanomaterials, one must not forget the called for a multifaceted strategy that includes critical role of design in ensuring that technology intensification of risk research, promotion of development occurs in parallel with technology social dialogue, development of a single piece of assessment. Nanotechnology development has nano‑specific legislation based on the precautionary occurred in the absence of clear design rules for principle, establishment of a labelling and product chemists and materials developers on how to register, and a reform of the current chemical, integrate health, safety and environmental concerns product and environmental legislation (SRU German into the design of nanomaterials. This is not Advisory Council for the Environment, 2011). surprising given that most chemists and materials designers are not trained to recognise these issues. In many ways, these recommendations echo those The emerging area of green nanotechnology offers made by the Royal Society and Royal Academy of promise for the future. For this type of focus on Engineering in 2004 in areas such as health, safety preventive design to occur, we will need a cultural and environmental impacts; regulatory, social and transition: that chemists and materials developers

550 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

are educated on health, safety and environment; as well as risk governance of nanotechnologies that environment, health and safety become quality and other emerging technologies, a common concerns in the development of new materials, denominator of all of these recommendations is that equal to economic and performance considerations; many of them are not or have yet to be successfully that research on the sustainability of materials is implemented by political decision-makers. As a funded at levels significant enough to identify early result, there remains a developmental environment warnings; and that regulatory systems provide that hinders the adoption of precautionary yet incentives for safer and sustainable materials. socially and economically responsive strategies in the field of nanotechnology. If left unresolved, When it comes to addressing R&D gaps, specific this has the potential to hamper our ability as a legislative gaps, limitations in current risk society to ensure the responsible development of assessment and risk management approaches nanotechnologies.

Table 22.2 Early warnings and actions

1974 Taniguchi first uses the term nanotechnology referring to the ability to engineer materials precisely at the nanometre (nm) level 1981 Scanning tunnelling microscope developed 1985 Atomic force microscope developed 1985 Fullerenes discovered at 1986 Drexler raises concern about potential risks of nanotechnology 1991 Iijima discovers carbon nanotubes 1992 Surface area found to be a better descriptor than mass for the adverse effects observed in rats

exposed to TiO2 2000 National Nanotechnology Initiative (NNI) established by the US Government 2003 Making analogies with ultrafine particles and asbestos, the Royal Society and Royal Academy of Engineering in the UK calls for more research and for avoidance of the release of manufactured nanoparticles and nanotubes into the environment 2004 Single-walled carbon nanotubes of different purity found to induced dose-dependent granulomas and interstitial inflammation in the lungs of mice 2006 Project for Emerging Nanotechnologies, Woodrow Wilson International Center for Scholars launches online consumer nanoproduct inventory totalling 212 products 2006 2 year voluntary reporting program set up in the United Kingdom by DEFRA 2007 Publication of Nano-risk framework jointly developed by the American non-governmental organisation Environmental Defense and the DuPont Corporation 2007 Voluntary reporting program set up in the US by the US EPA 2008 Long multi-walled carbon nanotubes are found to produce adverse effects qualitatively and quantitatively similar those caused by long asbestos 2009 Voluntary reporting program end in the US receiving only 31 submissions 2009 Cosmetic Regulation in Europe adopted that requires labelling and safety assessment of nanomaterials 2009 European Parliaments Environment Committee call for application of the no data, no market principle in regard to regulation of nanomaterials 2011 Australia explicitly moves to differentiate the requirements for some new industrial nanoscale chemicals in its National Industrial Chemicals Notification and Assessment Scheme

2011 NIOSH (2011) has determined that ultrafine TiO2 should be considered a potential occupational carcinogen 2011 European Commission publishes proposal of a definition of nanomaterials

Late lessons from early warnings: science, precaution, innovation 551 Emerging issues | Nanotechnology — early lessons from early warnings

References as a Regulatory Governance Mechanism for Nanotechnologies', Regulation & Governance, (2/3) Aitken, R.J., Hankin, S.M., Ross, B., Tran, C.L., 145–164. Stone, V., Fernandes, T.F., Donaldson, K., Duffin, R, Chaudhry, Q., Wilkins, T.A., Wilkins, S.A., Levy, Boxall, A.B.A., Chaudhry, Q., Sinclair, C., Jones, A., L.S., Rocks, S.A., Maynard, A., 2009, EMERGNANO: Aitken, R., Jefferson, B., Watts, C., 2008, Current and A review of completed and near completed environment, Future Predicted Environmental Exposure To Engineered health and safety research on nanomaterials and Nanoparticles, Central Science Laboratory, York. nanotechnology, Defra Project CB0409, IOM, Edinburgh, United Kingdom. Breggin, L., Falkner, R., Jaspers, N., Perdergrass, J., Porter, R., 2009, Securing the Promise of Aitken, R.A, Bassan, A., Friedrichs, S., Hankin, S.M., Nanotechnologies Towards Translatic Regulatory Hansen, S.F., Holmqvist, J., Peters, S.A.K., Poland, Cooperation, Royal Institute of International Affairs, C.A., Tran, C.L., 2011, Specific Advice on Exposure London. Assessment and Hazard/Risk Characterisation for Nanomaterials under REACH (RIP-oN 3) Final Project BSI, 2007, Terminology for carbon Nanostructures. PAS Report, Document reference RNC/RIP-oN3/FPR/1/ 134:2007, British Standards Institution, London. FINALBrussels: European Commission. CEC, 2008a, Communication From The Commission Baun, A., Hansen, S.F., 2008, 'Environmental To The European Parliament, The Council And challenges for ', Nanomedicine, (2/5) The European Economic And Social Committee 605–608. Regulatory Aspects Of Nanomaterials [Sec(2008) 2036] Com(2008) 366 final, Commission of the Baun, A., Hartmann, N.B, Greiger, K.D., Hansen, European Communities, Brussels. S.F., 2009, 'Setting the Limits for Engineered Nanoparticles in European Surface Waters', Journal CEC, 2008b, Proposal for a Regulation of the of Environmental Monitoring, (11) 1 774–1 781. European Parliament and of the Council on novel foods and amending Regulation (EC) [common Baun, A., Sørensen, S.N., Rasmussen, R.F., procedure] (presented by the Commission) Hartmann, N.B., Koch, C.B., 2008, 'Toxicity and [SEC(2008) 12] [SEC(2008) 13] COM(2007) 872 final bioaccumulation of xenobiotic organic compounds 2008/0002 (COD). 14-1 2008. Brussels, Commission of in the presence of aqueous suspensions of the European Communities. aggregates of nano-C60', Aquatic Toxicology, (86) 379–387. Cha, K., Hong, H. W., Choi, Y. G., Lee, M. J., Park, J. H., Chae, H. K., Ryu, G., Myung, H., 2008, Becker, L., Bada, J.L., Winans, R.E., Hunt, J.E., Bunch, 'Comparison of acute responses of mice livers to T.E, French, B.M., 1994, 'Fullerenes in the 1.85-billion- short-term exposure to nano-sized or micro-sized year-old Sudbury impact structure', Science, silver particles', Biotechnology Letter, (30/11) (265/5172) 642-645. 1 893–1 899.

Benn, T., Cavanagh, B., Hristovski, K., Posner, J.D., Chaudhry, Q, Gergely, A. and Bowman, D.M., 2012, Westerhoff, P., 2010, 'The Release of Nanosilver from 'Regulatory Frameworks for Food'. In: Bowman, Consumer Products Used in the Home', J. Environ. Qingrong Huang (ed), Nanotechnology in the food, Qual., (39) 1 875–1 882. beverage and nutraceutical industries, Woodhead Publishing, Sawston, pp. 85–101. Binning, G., Quate, C.F., Gerber, C.H., 1986, 'Atomic Force Microscope', Phys. Rev. Lett., (56/9) 930–933. Chaundry, Q., Blackburn, J., Floyd, P., George, C., Nwaogu, T., Boxall, A., Aitken, R., 2006, A scoping Binning, G., Rohrer, H., Gerber, C.H., Weibel, E., 1982, study to identify gaps in environmental regulation 'Surface Studies by Scanning Tunneling Microscopy', for the products and applications of nanotechnologies, Phys. Rev. Lett., (49/1) 57–61. Department for Environment, Food and Rural Affairs, London. Bowman, D.M. and G. van Calster, 2007, 'Has REACH Gone Too Far?', Nature Nanotechnology, (2/9) 525–526. ChemSec, 2011, European Commission adopts narrow recommendation on the definition of nanomaterial, Bowman, D.M. and G.A. Hodge, 2009, 'Counting 21 October 2011. on Codes: An Examination of Transnational Codes

552 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

Chen, H. and Roco, M.C., 2009, 'Government The National Nanotechnology Initiative Hearing Research Investment and Nanotechnology Before The Subcommittee On Research And Science Innovations: NSF Funding and USPTO Education Committee On Science And Technology Analysis, 2001–2004', Mapping Nanotechnology House Of Representatives One Hundred Tenth Innovations and Knowledge, (20) 1–30. Congress First Session October 31, 2007 Serial No. 110–69. Washington, D.C.: U.S. Government Chen, X., Schluesener, H.J., 2008, 'Nanosilver: Printing Office, 117–135. A nanoproduct in medical application', Toxicology Letters, (176/1) 1–12. Donaldson, K., Brown, D., Clouter, A., Duffin, R., MacNee, W., Renwick, L., Tran, L., Stone, V., 2002, Christensen, F.M., Johnston, H.J., Stone, V., Aitken, 'The pulmonary toxicology of ultrafine particles', R.J., Hankin, S., Peters, S., Aschberger, K., 2010, J. Aerosol Med., (15/2) 213–220. 'Nano-silver — feasibility and challenges for human health risk assessment based on open Drexler, K.E., 1986, Engines of Creation, The Coming literature', , (4/3) 284–295. Era of Nanotechnology, Anchor Books.

Cientifica, 2006, Nanotube Production Survey, ECHA, 2011, Silver Ecotoxicological Cientifica, London. Information.001, (http://apps.echa.europa.eu/ registered/data/dossiers/DISS-9d92ea78-89c7-2334- Cientifica, 2007, Half way to the trillion dollars, e044-00144f67d249/AGGR-f5e8ac40-6d22-4771- Cientifica, London. a415-f7f65ef3928a_DISS-9d92ea78-89c7-2334-e044- 00144f67d249.html#AGGR-f5e8ac40-6d22-4771-a415- Commission Recommendation of 18 October 2011 f7f65ef3928a) accessed 28 January 2012. on the definition of nanomaterial (2011/696/EU), Official Journal of the European Union, 275/38-40. ED and DuPont, 2007, Nano Risk Framework, Environmental Defense and DuPont. Crocetti, G., Miller, G., 2011, Nano-Silver: policy failure puts at risk, Friends of the Earth, EEA, 2001, Late lessons from early warnings: the Melbourne. precautionary principle 1896–2000, Environmental issue report No 22, European Environment Agency. Davies, J.C., 2006, Managing The Effects Of Nanotechnology, Project on Emerging Ellinger-Ziegelbauer., H, Pauluhn, J., 2009, Nanotechnologies, Woodrow Wilson International 'Pulmonary toxicity of multi-walled carbon Center For Scholars, Washington, D.C. nanotubes (Baytubes®) relative to quartz following a single 6h inhalation exposure of rats and a 3 months DEFRA, 2008, The UK Voluntary Reporting Scheme post-exposure period', Toxicology, (266) 16–29. for Engineered Nanoscale materials: Seventh Quarterly Report, Department for Environment, Food and EPA OIG, 2011, EPA Needs to Manage Nanomaterial Rural Affairs, London. Risks More Effectively, U.S. Environmental Protection Agency Office of Inspector General, Washington, Denison, R., 2007a, Statement of Dr. Richard A. D.C. Denison, Senior Scientist, Environmental Defense. Research On Environmental And Safety Impacts Of EurActiv, 2011, EU plays down expectations on REACH Nanotechnology: Current Status Of Planning And review. Implementation Under The National Nanotechnology Initiative Hearing Before The Subcommittee On European Parliament, 2009, European Parliament Research And Science Education Committee On legislative resolution of 24 March 2009 on Science And Technology, House Of Representatives the proposal for a regulation of the European One Hundred Tenth Congress First Session Parliament and of the Council on cosmetic products 31 October 2007 Serial No. 110–69. Washington, D.C.: (recast) (COM(2008)0049 — C6-0053/2008 — US Government Printing Office, 57–66. 2008/0035(COD)).

Denison, R., 2007b, Answers to Post-Hearing European Parliament and the Council of the Questions of Dr. Richard A. Denison, Senior Scientist, European Union (EP and CEU), 2006, Regulation Environmental Defense. Research On Environmental (EC) No. 1907/2006 of the European Parliament And Safety Impacts Of Nanotechnology: Current and of the Council of 18 December 2006 concerning Status Of Planning And Implementation Under the Registration, Evaluation, Authorization and

Late lessons from early warnings: science, precaution, innovation 553 Emerging issues | Nanotechnology — early lessons from early warnings

Restriction of Chemicals (REACH), establishing a Hankin, S.M., Peters, S.A.K., Poland, C.A., Foss European Chemicals Agency, amending Directive Hansen, S., Holmqvist, J., Ross, B.L., Varet, J. 999/45/EC and repealing Council Regulation (EEC) and Aitken, R.J., 2011, Specific Advice on Fulfilling No. 793/93 and Commission. Information Requirements for Nanomaterials under REACH (RIP-oN 2) — Final Project Report. Document Ferin, J., Oberdörster, G., Penney, D.P., Soderholm, reference RNC/RIP-oN2/FPR/1/FINAL. Brussels: S.C., Gelein, R ., Piper, H.C., 1990, 'Increased Eurropean Commission. pulmonary toxicity of ultrafine particles? I. Particle clearance, translocation, morphology', J. of Aerosol Hansen, S. F., Larsen, B. H., Olsen, S. I., Baun, A., Sci., (21/3) 381–384. 2007, 'Categorization framework to aid Hazard Identification of Nanomaterials', Nanotoxicol, Fiedler, F.A. and Reynolds, G.H., 1994, 'Legal (1) 243–250. Problems of Nanotechnology: An Overview', Southern California Interdisciplinary Law Journal, (3) Hansen, S. F., Tickner, J. A., 2007, 'The Challenges 594–629. of Adopting Voluntary Health, Safety and Environment Measures for Manufactured Fortner, J. D., Lyon, D. Y., Sayes, C. M., Boyd, A. M., Nanomaterials. Lessons from the past for more Falkner, J. C., Hotze, E. M., Alemany, L. B., Tao, Y. effective adoption in the future', Nanotech Law & J., Guo, W., Ausman, K. D., Colvin, V. L., Hughes, J. Business, (4/3) 341–359. B., 2005, 'C-60 in water: formation and microbial response', Environ Sci & Technol, (39/11) Hansen, S.F., 2009, Regulation and risk assessment 4 307–4 316. of nanomaterials: Too little, too late? PhD thesis, Technical University of Denmark, Department of Franco, A., Hansen, S.F., Olsen, S.I., Butti, L., 2007, Environmental Engineering, Kgs. Lyngby. 'Limits and Prospects of the Incremental Approach and the European Legislation on the Management of Hansen, S.F., Nielsen, K.N., Knudsen, N., Grieger, Risks related to Nanomaterials', Regul. Toxico Pharm., K.D. and Baun, A., 2012, 'Operationalization (48) 171–183. and application of "early warning signs" to screen nanomaterials for harmful properties', Fujitani, Y., Kobayashi, T., Arashidani, K., Kunugita, Environmental Science: Processes & Impacts, N., Suemura, K., 2008, 'Measurement of the Physical doi:10.1039/C2EM30571B (in press). Properties of Aerosols in a Factory for Inhalation ', J. Occup. Environ. Heinrich, U., Fuhst, R., Rittinghausen, S., Hyg., (5/6) 380–389. Creutzenberg, O., Bellmann, B., Koch, W., Levsen, K., 1995, 'Chronic inhalation exposure of Wistar rats Gavelin, K., Wilson, R., and Donaldson, R., 2007, and two different strains of mice to dieselengine Democratic technologies? The final report of the exhaust, carbon black, and titanium dioxide', Inhal. Nanotechnology Engagement Group (NEG), Involve, Toxicol., (7/4) 533–556. London. Hodge, G.A., Bowman, D.M. and Maynard, A.D. Gottschalk, F., Sonderer, T., Scholz, R.W., (eds), 2010, International Handbook on Regulating Nowack, B., 2010b, 'Possibilities and limitations of Nanotechnologies, Edward Elgar, Cheltenham. modeling environmental exposure to engineered nanomaterials by probabilistic material flow Hu, Z., 2010, Impact of Silver Nano-particles on analysis', Environmental Toxicology and Chemistry, (29) Wastewater Treatment, WERF Report U3R07, IWA 1 036–1 048. Publishing, London, United Kingdom.

Grieger, K., Hansen, S.F., Baun, A., 2009, 'The Huczko, A., Lange, H., Calko, E., Grubek-Jaworska, known unknowns of nanomaterials: Describing and H., Droszcz, P., 2001, 'Physiological testing of carbon characterizing uncertainty within environmental, nanotubes: are they asbestos-like?', Full Sci & Tech, health and safety risks', Nanotoxicology, (3/3) 1–12. (9/2) 251–254.

Griffitt, R.J., Luo, J., Gao, J., Bonzongo, J.C. and IRGC, 2006, White paper on Nanotechnology Risk Barber, D.S., 2008, 'Effects of particle composition Governance, International Risk Governance Council, and species on toxicity of metallic nanomaterials Geneva. in aquatic organisms', Environmental Toxicology and Chemistry, (27/9) 1 972–1 978.

554 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

IRGC, 2007, Nanotechnology Risk Governance: Frontiers in Regulation: The Age of Nanotechnology, Recommendations for a global, coordinated approach to Edward Elgar, Cheltenham, pp. 149–165. the governance of potential risks, International Risk Governance Council, Geneva. Linkov, I., Satterstrom, F. K., Monica Jr., J.C., Hansen, S.F., Davis, T.A., 2009, 'Nano Risk Governance: Igami, M. and Saka, A., 2007, Capturing the Evolving Current Developments And Future Perspectives', Nature of Science, Development of New Scientific Nanotech Law & Business, (6) 203–220. Indicators and Mapping of Science, STI Working Paper 2007/1, OECD Directorate for Science, Technology Ludlow, K., Bowman, D.M. and Kirk, D., and Industry. 2009, 'Hitting the mark or falling short with nanotechnology regulation?', Trends in Biotechnology, Iijima, S., 1991, 'Helical Micro-tubules of Graphitic (27/11) 615–620. Carbon', Nature, (345) 56–58. Luoma, S. N., 2008, Silver Nanotechnologies and ISO, 2008, Nanotechnologies — Terminology and the Environment Old Problems or New Challenges? definitions for nano-objects — , nanofibre PEN 15, Project on Emerging Nanotechnologies, and nanoplate, ISO/TS 27687:2008, International Woodrow Wilson International Center for Scholars, Organization for Standardization, Geneva. Washington, DC.

Kagan, V. E., Tyurina, Y. Y., Tyurin, V. A., Konduru, Lynch, J., 2006, 'Its not easy being interdisciplinary', N. V., Potapovich, A. I., Osipov, A.N., Kisin, E. R., Int. J. Epidemiol., (35) 1 119–1 122. Schwegler-Berry, D., Mercer, R., Castranova, V., Shvedova, A. A., 2006, 'Direct and indirect effects Lux Research, 2008, Nanomaterials State of the Market of single walled carbon nanotubes on RAW 264.7 Q1 2009: Cleantechs Dollar Investments, Penny Returns, macrophages: Role of iron', Toxicol. Lett., (165/1) Lux Research, . 88–100. Madl, A.K., Pinkertin, K.E., 2009, 'Health effects of Karn, B., Roco, M., Masciangioli, T. and Savage, N., inhaled engineered and incidental nanoparticles', 2003, Nanotechnology and the Environment Report of a Critical Reviews in Toxicology, (39/8) 629–658. National Nanotechnology Initiative Workshop (National Science and Technology Council/Committee on Ma-Hock, L., Treumann, S., Strauss. V., Brill, S., Technology/Subcommittee on Nanoscale Science, Luizi, F., Mertler, M., Wiench, K., Gamer, A.O., Engineering and Technology, Arlington, Virginia. Ravenzwaay, B., Landsiedel, R., 2009, 'Inhalation toxicity of multi-wall carbon nanotubes in rats Kim, Y.S., Kim, J.S., Cho, H.S., Rha, D.S., Park, J.D., exposed for 3 months', Toxicol. Sci., (112/2) 468–481. Choi, B.S., Lim, R., Chang, H.K., Chung, Y.H., Kwon, I.H., Jeong, J., Han, B.S., Yu, I.J., 2008, 'Twenty- Matus, K.J.M., Hutchison, J.E., Peoples, R., Rung, S., eight‑day oral toxicity, genotoxicity, and gender- Tanguay, RL., 2011, Green Nanotechnology Challenges related tissue distribution of silver nanoparticles in And Opportunities. ACS Chemistry for Life, ACS Sprague-Dawley rats', Inhal. Toxicol., (20) 575–583. Institute.

Kleiner, K., Hogan, J., 2003, 'How safe is nanotech', Maynard, A., 2006, Nanotechnology: A Research New Scientist, (177/2388). Strategy for Addressing Risk. Project on Emerging Nanotechnologies, Woodrow Wilson International Kroto, H.W., Heath, J.R., OBrien, S.C., Curl, R.F. and Center for Scholars, Washington, D.C. Smalley, R.E., 1985, 'C60: ', Nature, (318) 162–163. Maynard, A. D., 2011, 'Regulators: Dont define nanomaterials', Nature, (475) 31. Lam, C. W, James, J. T., McCluskey, R., Hunter, R. L., 2004, 'Pulmonary Toxicity of Single-Wall Carbon Maynard, A. D., Warheit, D., Philbert, M. A., 2011, Nanotubes in Mice 7 and 90 Days After Intratracheal 'The New Toxicology of Sophisticated Materials: Instillation', Toxicol Sci, (77) 126–134. Nanotoxicology and Beyond', Toxicological Sciences, (120/1) S109–S129. Levi-Faur, D., Comhanester, H., 2007, The risks of regulation and the regulation of risks: The Maynard, A., Rejeski, D., 2009, 'Too small to governance of nanotechnology in: Hodge, G.A., overlook', Nature Nanotechnology, (460) 174. Bowman, D.M. and Ludlow, K. (eds) New Global

Late lessons from early warnings: science, precaution, innovation 555 Emerging issues | Nanotechnology — early lessons from early warnings

Maynard, A.D, Bowman, D.M. and Hodge, G.A., Mullins, S., 2010, Are we willing to heed the 2011, 'The wicked problem of regulating sophisticated lessons of the past? Nanomaterials and Australias materials', Nature Materials, (10) 554–557. asbestos legacy, in: M Hull and D Bowman D (eds) Nanotechnology Environmental Health and Safety: Maynard, A.D. and Aitken, R.J., 2007, 'Assessing Risks, Regulation and Management, Elsevier, Oxford, exposure to airborne nanomaterials: Current abilities pp. 49–69. and future requirements', Nanotoxicol., (1/1) 26–41. Murr, L.E., Esquivel, E.V. Bang, J.J., de la Rosa, Maynard, A.D., Aitken, R.J., Butz, T., Colvin, V.L., G. Gardea-Torresdey, J.L., 2004, 'Chemistry and Donaldson, K., Oberdörster, G., Philbert, M.A., nanoparticulate compositions of a 10,000 year-old ice Ryan, J., Seaton, A., Stone, V., Tinkle, S.S., Tran, L., core melt water', Water Research, (38/19) 4 282–4 296. Walker, N., Warheit, D.B., 2006, 'Safe Handling of Nanomaterials', Nature, (444) 267–269. ISO, 2008, Nanoparticle, nanofibre and nanoplate, ISO/TS 27687:2008, International Organization for Meili, C. and M. Widmer, 2010, Voluntary measures Standardization, Geneva. in nanotechnology risk governance: the difficulty of holding the wolf by the ears, in: Hodge, Nanowerk, 2010, Company & Labs Directory, (http:// G.A., Bowman, D.M. and Maynard, A.D. (eds), www.nanowerk.com/nanotechnology/research/ International Handbook on Regulating Nanotechnologies, nanotechnology_links.php) accessed 12 December Edward Elgar, Cheltenham, pp. 446–461. 2011.

Mikkelsen, S.H., Hansen, E., Christensen, T.B., National Academy of Sciences, 2012, A Research Baun, A., Hansen, S.F., Binderup, M.L., 2011, Strategy for Environmental, Health, and Safety Aspects Survey on basic knowledge about exposure and potential of Engineered Nanomaterials, Committee to Develop environmental and health risks for selected nanomaterials, a Research Strategy for Environmental, Health, Environmental Project 1370. Danish Ministry of the and Safety Aspects of Engineered Nanomaterials; Environment Danish Protection Agency. National Research Council, The National Academy Press, Washington, D.C. Milieu and RPA, 2009, Information from Industry on Applied Nanomaterials and their Safety. NNI, 2008, Strategy for Nanotechnology-Related Deliverable 1 prepared for European Commission Environmental, Health and Safety Research, National DG Environment. Nanotechnology Initiative, Washington D.C.

Milmo, S., 2009, Nanomaterials cause classification NNI, 2009, So what is nanotechnology?, National headache for Reach, Royal Society of Chemistry Nanotechnology Initiative, Washington D.C. 16 June 2009. NICNAS, 2010, 'Adjustments to NICNAS new Moore, M. N., 2006, Do nanoparticles present chemical processes for industrial nanomaterials', ecotoxicological risks for the health of the aquatic Chemical Gazette, No. C 10, 14–16. environment?, Environ. Int., (32) 967–976. NIOSH, 2011, Current Intelligence Bulletin 63 Mueller, N.C., Nowack, B., 2008, Exposure modeling Occupational Exposure To Titanium Dioxide, of engineered nanoparticles in the environment, Department Of Health And Human Services Centers Environmental Science & Technology, (42) 4 447–4 453. For Disease Control And Prevention National Institute For Occupational Safety And Health, Muilerman, H., Tweedale, T., 2011, A Toxic Mixture Washington, D.C. Industry bias found in EFSA working group on risk assessment for toxic chemicals, Pesticide Action Oberdorster, G., Oberdorster, E. and Oberdorster, Network Europe (PAN Europe). J., 2005a, 'Nanotoxicology: An emerging discipline evolving from studies of ultrafine particles', Environ. Muller, J., Huaux, F., Moreau, N., Misson, P., Heilier, Health Perspect., (113) 823–839. J.F., Delos, M., Arras, M., Fonseca, A., Nagy, J.B., Lison, D., 2005, Respiratory toxicity of multi-wall Oberdörster, G., Ferin, J., Finkelstein, G., Wade, P. carbon nanotubes, Toxicol. Appl. Pharmacol., (207/3) and Corson, N., 1990, 'Increased pulmonary toxicity 221–231. of ultrafine particles? II. Lung lavage studies', J. Aerosol Sci., (21/3) 384–387.

556 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

Oberdörster, G., Ferin, J., Gelein, R., Soderholm, Pronk, M.E.L., Wijnhoven, S.W.P. Bleeker, E.A. S. C., Finkelstein, G., 1992, 'Role of the alveolar Heugens, E.H.W. Peijnenburg, W.J.G.M Luttik, R. macrophage in lung injury: studies with ultrafine Hakkert, B.C., 2009, Nanomaterials under REACH. particles', Environ. Health Perspect., (97) 193–199. Nanosilver as a case study, RIVM (the National Institute for Public Health and the Environment in Oberdörster, G., Maynard, A., Donaldson, K., The Netherlands). Castranova, V., Fitzpatrick, J., Ausman, K., Carter, J., Karn, B., Kreyling, W., Lai, D., Olin, S., Monteiro- Poland, C. A., Duffin, R., Kinloch, I., Maynard, A., Riviere, N., Warheit, D., Yang, H., 2005b, 'Principles Wallace, W. A. H., Seaton, A., Stone, V., Brown, for characterizing the potential human health effects S., Macnee, W., Donaldson, K., 2008, 'Carbon from exposure to nanomaterials: Elements of a Nanotubes Introduced Into The Abdominal Cavity screening strategy', Partic Fibre Toxicol., (2) 8. Ofmice Show Asbestoslike Pathogenicity In A Pilot Study', Nat. Nanotechnol., (3) 423–428. Oberdorster, G., Stone, V., Donaldson, K., 2007, 'Toxicology of nanoparticles: A historical Pope, C.A III. and Dockery, D.W., 2006, 'Health perspective', Nanotoxicol., (1/1) 2–25. effects of fine particulate : Lines that connect', J. Air Waste Manag Assoc., (56) 709–742. Official Journal of the European Union, 2011, Commission Recommendation of 18 October 2011 RCEP, 2008, Twenty-seventh Report Novel Materials on the definition of nanomaterial (2011/696/EU), in the Environment: The case of nanotechnology Official Journal of the European Union, 275/38-40. Royal Commission on Environmental Pollution, The Stationery Office, Norwich. Organisation for Economic Co-operation and Development, 2009, Environment Directorate Roberts, A.P., Mount, A.S., Seda, B., Souther, J., Joint Meeting Of The Chemicals Committee and Qiao, R., Lin, S.J., Ke, P.C., Rao, A.M. & Klaine, S.J., the Working Party On Chemicals, Pesticides 2007, 'In vivo biomodification of lipid-coated carbon And Biotechnology Series on the Safety Of nanotubes by Daphnia magna', Environ. Sci. Technol., Manufactured Nanomaterials Number 9 (41/8) 3 025–3 029. EHS Research Strategies On Manufactured Nanomaterials: Compilation of Outputs. ENV/JM/ Roco, M. C. and Bainbridge, W.S., 2005, 'Societal MONO(2009)10, 14 May 2009, OECD, Paris. implications of nanoscience and nanotechnology: Maximizing human benefit', J. Nanopart Res., (7/1)1–13. Organisation for Economic Co-operation and Development, 2009, Environment Directorate Roco, M. C. and Renn, O., 2006, 'Nanotechnology Joint Meeting Of The Chemicals Committee and and the need for risk governance', J. Nanopart Res., the Working Party On Chemicals, Pesticides (8) 153–191. And Biotechnology Current Developments In Delegations and other International Organisations Roco, M. and Bainbridge, W.S., 2001, Societal on the Safety Of Manufactured Nanomaterials — implications of Nanoscience and Nanotechnology, Tour De Table. ENV/JM/MONO(2009)23, 9 July Kluwer, Dordrecht, the Netherlands. 2009, OECD, Paris. Roco, M.C., 2011, 'Nanotechnology Research Osier, M. and Oberdorster, G., 1997, 'Intratracheal Directions for Societal Needs in 2020', Science Policy Inhalation vs Intratracheal Instillation: Differences Reports, 2011, vol. 1, 1–28, doi:10.1007/978-94- in Particle Effects', Fundamental and Applied 007-1168-6_1 The Long View of Nanotechnology Toxicology, (40) 220–227. Development: The National Nanotechnology Initiative at 10 Years. Pauluhn, J., 2010, 'Subchronic 13-week inhalation exposure of rats to multiwalled carbon nanotubes: Rossi, M., Tickner, J., Geiser, K., 2006, Alternatives Toxic effects are determined by density of Assessment Framework Version 1.0, Lowell Centre for agglomerate structures, not fibrillar structures', Substainable Production. Toxicol. Sci., (113/1) 226–242. RS and RAE, 2004, Nanoscience and Nanotechnologies: PEN, 2011, Consumer Products An inventory of Opportunities and Uncertainties, Royal Society & nanotechnology-based consumer products currently on Royal Academy of Engineering, Royal Society, the market. Project on Emerging Nanotechnologies. London.

Late lessons from early warnings: science, precaution, innovation 557 Emerging issues | Nanotechnology — early lessons from early warnings

Sayes, C. M., Fortner, J. D., Guo, W., Lyon, D., Boyd, Shvedova, A. A., Kisin, E. R., Mercer, R., Murray, A. M., Ausman, K. D., Tao, Y. J., Sitharaman, B., A. R., Johnson, V. J., Potapovich, A.I., Tyurina, Y. Wilson, L. J., Hughes, J. B., West, J. L., Colvin, V. L., Y., Gorelik, O., Arepalli, S., Schwegler-Berry, D., 2004, 'The differential cytotoxicity of water-soluble Hubbs, A. F., Antonini, J., Evans, D. E., Ku, B. K., fullerenes', Nano Lett., (4/10) 1 881–1 887. Ramsey, D., Maynard, A., Kagan, V. E., Castranova, V., Baron, P., 2005, 'Unusual inflammatory and Sayes, C. M., Reed, K. L., Warheit, D. B., 2007, fibrogenic pulmonary responses to single-walled 'Assessing Toxicity of Fine and Nanoparticles: carbon nanotubes in mice', Am. J. Physiol. Lung Cell Comparing In Vitro Measurements to In Vivo Mol. Physiol., (289) 698–708. Pulmonary Toxicity Profiles', Toxicol. Sci., (97/1) 163–180. Smith, C.J., Shaw, B.J. & Handy, R.D., 2007, 'Toxicity of single walled carbon nanotubes to rainbow trout, Sayes, C.M., Fortner, J.D., Guo, W., Lyon, D., Boyd, (Oncorhynchus mykiss): Respiratory toxicity, organ A.M., Ausman, K.D., Tao, Y.J., Sitharaman, B., pathologies, and other physiological effects', Aquatic Wilson, L.J. Hughes, J.B., West, J.L., Colvin, V.L., Toxicology, (82/2) 94–109. 2004, 'The differential cytotoxicity of water-soluble fullerenes', Nano Lett., (4) 1 881–1 887. SRU German Advisory Council on the Environment, 2011, Precautionary Strategies for Managing SCENIHR, 2006, Scientific Committee on Emerging Nanomaterials Summary for policy makers. and Newly Identified Health Risks (SCENIHR), modified Opinion (after public consultation) on Stamm, H., 2011, 'Risk factors: Nanomaterials should The appropriateness of existing methodologies to be defined', Nature, (476) 399. assess the potential risks associated with engineered and adventitious products of nanotechnologies, Stokes, E., Bowman, D.M., forthcoming 2012, European Commission Health & Consumer 'Regulatory Inheritance and Emerging: Technologies: Protection Directorate-General, Brussels. The Case of Nanotechnologies and ', European Journal of Risk Regulation. SCENIHR, 2007, Scientific Committee for Emerging and Newly-Identified Health Risks (SCENIHR) The Stone, V., Hankin, S., Aitken, R., Aschberger, K., appropriateness of the risk assessment methodology Baun, A., Christensen, F., Fernandes, T., Hansen, in accordance with the Technical Guidance S.F., Hartmann, N.B., Hutchinson, G., Johnston, H., Documents for new and existing substances for Micheletti, G., Peters, S., Ross, B., Sokull-Kluettgen, assessing the risks of nanomaterials, European B., Stark, D., Tran, L., 2010, Engineered Nanoparticles: Commission Health & Consumer Protection Review of Health and Environmental Safety (ENRHES). Directorate-General, Brussels. Sung J.H., Ji J.H., Yoon J.U., Kim D.S., Song M.Y., SCENIHR, 2009, Risk Assessment of Products of Jeong J., Han B.S., Han J.H., Chung Y.H., Kim J., Nanotechnologies, Scientific Committee for Emerging Kim T.S., Chang H.K., Lee E.J., Lee J.H., Yu I.J., and Newly-Identified Health Risks (SCENIHR), 2008, 'Lung function changes in Sprague-Dawley European Commission Health & Consumer rats after prolonged inhalation exposure to silver Protection Directorate-General, Brussels. nanoparticles', Inhal. Toxicol., (20) 567–574.

Schmidt, K., 2007, NanoFrontiers: Visions for the Sylvester, D.J. and Bowman, D.M., 2011, Navigating Future of Nanotechnology, Project on Emerging the Patent Landscapes for Nanotechnology: English Nanotechnologies, Woodrow Wilson Center for Gardens or Tangled Grounds?, in: Sarah J Hurst (ed), International Scholars, Washington D.C. Biomedical Nanotechnology: Methods and Protocols, Springer, New York, pp. 359–378. Schylter, C., 2009, Report on regulatory aspects of nanomaterials (2008/2208(INI)) Committee on the Taniguchi, N., 1974, On the Basic Concept of Nano- Environment, Public Health and Food Safety, Technology, Proceedings of the. Intl. Conf. Prod. London, RR\418270EN.doc, European Parliament, Brussels. Part II, British Society of Precision Engineering.

Seaton, A., Tran, L., Aitken, R., Donaldson, K., 2009, Technology Transfer Center, 2007, Government Nanoparticles, human health hazard and regulation, Funding, Companies And Applications in: Journal of the Royal Society Interface, doi:10.1098/ Nanotechnology Worldwide 2007, Technology Transfer rsif.2009.0252.focus. Center.

558 Late lessons from early warnings: science, precaution, innovation Emerging issues | Nanotechnology — early lessons from early warnings

Thayer, A.M., 2007, Carbon Nanotubes by the Metric Warheit, D. B., Webb, T. R., Sayes, C. M., Colvin, V. Ton, Chemical & Engineering News, (85/46) 29–35. L., Reed, K. L., 2006, 'Pulmonary instillation studies

with nanoscale TiO2 rods and dots in rats: toxicity is Tsuji, J.S., Maynard, A.D., Howard, P.C., James, not dependent upon particle size and surface area', J.T., Lam, C.W., Warheit, D.B., Santamaria, A.B., Toxicol. Sci., (91/1) 227–236. 2006, 'Research strategies for safety evaluation of nanomaterials, Part IV: Risk assessment of Weiss, R., 2006, Washington Post A01, 8 April 2006. nanoparticles', Toxicol. Sci., (89) 42–50. Widmer, M. and Meili, C., 2010, Approaching the US EPA, 2007, Inventory Status of Nanoscale nanoregulation problem in chemical legislation in Substances — General Approach January 23, 2008. the EU and US, in GA Hodge, DM Bowman and AD Maynard (eds), International Handbook on Regulating US EPA, 2009a, Significant New Use Rules on Certain Nanotechnologies, Cheltenham: Edward Elgar, Chemical Substances 40 CFR Part 721. Federal pp. 238–267. Register 74(120): 29982-29998 (http://www.epa.gov/ fedrgstr/EPA-TOX/2009/June/Day-24/t14780.pdf) Wijnhoven, S.W.P., Peijnenburg, W.J.G.M., Herberts, accessed 6 March 2012. C.A., Hagens, W.I., Oomen, A.G., Heugens, E.H.W, Roszek, B., Bisschops, J., Gosens, I., Van De Meent, US EPA, 2009b, Enhancing EPAs Chemical D., Dekkers, S., De Jong, W.H., Van Zijverden, Management Program. M., Sips, A.J.A.M., & Geertsma, R.E., 2009, 'Nano- silver — a review of available data and knowledge Warheit, D., 2009, 'Long-term Inhalation Toxicity gaps in human and environmental risk assessment', Studies with Multiwalled Carbon Nanotubes: Closing Nanotoxicology, (3/2) 109–138. the Gaps or Initiating the Debate?', Toxicol. Sci., (112/2) 273–275. Youtie, J., Shapira, P. and Porter, A. L., 2008, 'Nanotechnology publications and citations by Warheit, D. B., Laurence, B. R., Reed, K. L., Roach, leading countries and blocs', Journal of Nanoparticle D. H., Reynolds, G. A. M., Webb, T. R., 2004, Research, (10/6) 981–986. 'Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats', Toxicol. Sci., Zhenxia W., Xuepeng, L., Wenmin, W., Xunjiang, (77/1) 117–125. X., Tang, Z.C., Huang R.-B., Zheng L.-S. 1998. 'Fullerenes in the fossil of dinosaur egg', Fullerene science and technology, (6/4) 715–720.

Late lessons from early warnings: science, precaution, innovation 559